Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.

Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.

Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at [email protected].

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at [email protected].

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at [email protected].

Dietary intake of polyunsaturated fatty acids (PUFA), particularly omega 6, is associated with improved cognitive function in older adults, new research suggests.

The study provides important “pieces of the puzzle” of the diet and cognition connection, but the results aren’t “ready for prime time,” study investigator Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“I don’t think we’re there yet when it comes to recommending supplementation to the general public,” said Dr. McIntyre, adding a larger “more compelling study” is needed.

The study was published online Jan. 14 in The American Journal of Geriatric Psychiatry.
 

Clinically meaningful?

Research shows that 25%-50% of community-dwelling adults aged 65-85 years have some cognitive impairment. Other evidence indicates cognition is affected by dietary fat intake.

Many lines of research show that alterations in lipid homeostasis can cause brain dysfunction, said Dr. McIntyre. “This shouldn’t surprise us because our brain is made up of protein, water, and fat.”

This new analysis used combined data from the 2011-2012 and 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES), a series of ongoing cross-sectional surveys conducted by the Centers for Disease Control and Prevention. The data are collected in two phases, an in-home face-to-face interview and a physical examination.

Researchers obtained dietary intake information through two 24-hour dietary recall interviews. Dietary information included total energy (kcal/d), intakes in grams per day (g/d) of total fat, saturated fatty acid (SFAT), monounsaturated fatty acid (MUFA), PUFA, total omega-3 and total omega-6 fatty acids, and milligrams per day (mg/d) of cholesterol.

For cognitive function, the researchers used total and delayed recall scores of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), the animal fluency test, and the digit symbol substitution test (DSST).

The study included 2,253 adults aged 60 years and older (mean age, 69.4 years) and 51% were non-Hispanic White individuals.

After adjustment for age, sex, race/ethnicity, educational attainment, smoking status, alcohol consumption, income, and total energy, dietary intake of PUFA and omega-6 fatty acid was positively associated with DSST.

The DSST score increased about 0.06 standard deviation (SD) (about 1 score) with each SD increase in these fatty acids (8.8 g/d for PUFA and 7.9 g/d for omega-6) (P values were .02 for PUFA and .01 for omega-6).

However, it’s unclear what an improvement of 1 DSST score means clinically, said Dr. McIntyre. “The P value is significant, but how does that translate? Does this mean a person can now think more clearly or function better?”
 

‘Million dollar question’ remains unanswered

The fact that omega-6, considered neuroinflammatory, was associated with improved DSST score illustrates the complexity of this field, said Dr. McIntyre.

“We’re learning that when it comes to inflammation, many of the molecules in our brain that are implicated as anti-inflammatory can also be pro-inflammatory, so bad guys can be good guys and good guys can be bad guys.”

It speaks to the notion of homeostasis, he added. “Just like a seesaw; when you push this part down, that part goes up.”

The analysis showed the animal fluency score increased about 0.05 SD (around 0.3 score) with each SD (1.1 g/d) increase in dietary intake of omega-3.

There were no significant associations between other dietary fat intake and cognitive performance.

The researchers investigated the role of oxidative stress and antioxidant biomarkers (gamma glutamyl transpeptidase [GGT], bilirubin, uric acid, and vitamin D).

Cells produce oxidative radicals that are normally “mopped up” by our “innate antioxidant capability,” said Dr. McIntyre. “But in states of cognitive impairment, these oxidative stress markers accumulate and they exceed what the normal innate response is able to manage.”

The study showed GGT levels decreased with increased PUFA and omega-6 fatty acid intakes; levels of bilirubin decreased with increase in most dietary fat intakes; uric acid levels decreased with MUFA intake and omega-6/omega-3 ratio; and vitamin D levels increased with omega-3 fatty acid intake but decreased with SFAT intake.

Causal mediation analysis showed the association between dietary intake of fatty acids and DSST performance was partially mediated by GGT levels. However, Dr. McIntyre emphasized that this does not prove causality.

“The million dollar question is, is this the sole explanation for the association? In other words, is it the oxidative stress that caused the cognitive impairment and therefore correcting it improved it, or is it the case that oxidative stress is a proxy of other activities that are also taking place?”
 

A ‘plausible’ link

In an editorial, Candida Rebello, PhD, of the department of integrated physiology and molecular medicine at Pennington Biomedical Research Center, Baton Rouge, La., said the finding that omega-3 and omega-6 fatty acids are positively associated with cognition in older adults makes some sense.

She noted that aging is associated with an overt inflammatory phenotype, and evidence shows these fatty acids are precursors for bioactive molecules that play a role in self-limiting the acute inflammatory response.

Dr. Rebello said the positive association of omega-6 fatty acid with cognition shown in this study contrasts with the “common belief” that increasing dietary intake of these fatty acids enhances inflammation, but agreed the association is “plausible.”

She said it’s “essential” to determine “the underlying mechanisms that regulate the diverse features of inflammation and sort out the processes that protect from neuronal damage and those that contribute towards it.”

She noted the ratio of omega-6 to omega-3 is about 15:1 in the present day Western diet, as opposed to a 1:1 ratio in diets of the past. Omega-3 fatty acids are found in fish oil supplements and fatty fish like mackerel and salmon, while cereal, grains, and vegetable oil are sources of omega-6.

Attaining a measure of balance of fatty acids in the diet may be a “prudent approach,” said Dr. Rebello. “Substituting some meat entrées with fatty fish and polyunsaturated vegetable oils with monounsaturated fats such as olive oil are small changes that are likely to garner adherence.”

Dr. Rebello noted that the study used NHANES food intake data, which rely on participant self-report and so may not be accurate.

The study received funding from the MOE (Ministry of Education in China) Project of Humanities and Social Sciences and the Research Startup Fund of Southwest University. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, and AbbVie. He is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Dietary intake of polyunsaturated fatty acids (PUFA), particularly omega 6, is associated with improved cognitive function in older adults, new research suggests.

The study provides important “pieces of the puzzle” of the diet and cognition connection, but the results aren’t “ready for prime time,” study investigator Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“I don’t think we’re there yet when it comes to recommending supplementation to the general public,” said Dr. McIntyre, adding a larger “more compelling study” is needed.

The study was published online Jan. 14 in The American Journal of Geriatric Psychiatry.
 

Clinically meaningful?

Research shows that 25%-50% of community-dwelling adults aged 65-85 years have some cognitive impairment. Other evidence indicates cognition is affected by dietary fat intake.

Many lines of research show that alterations in lipid homeostasis can cause brain dysfunction, said Dr. McIntyre. “This shouldn’t surprise us because our brain is made up of protein, water, and fat.”

This new analysis used combined data from the 2011-2012 and 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES), a series of ongoing cross-sectional surveys conducted by the Centers for Disease Control and Prevention. The data are collected in two phases, an in-home face-to-face interview and a physical examination.

Researchers obtained dietary intake information through two 24-hour dietary recall interviews. Dietary information included total energy (kcal/d), intakes in grams per day (g/d) of total fat, saturated fatty acid (SFAT), monounsaturated fatty acid (MUFA), PUFA, total omega-3 and total omega-6 fatty acids, and milligrams per day (mg/d) of cholesterol.

For cognitive function, the researchers used total and delayed recall scores of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), the animal fluency test, and the digit symbol substitution test (DSST).

The study included 2,253 adults aged 60 years and older (mean age, 69.4 years) and 51% were non-Hispanic White individuals.

After adjustment for age, sex, race/ethnicity, educational attainment, smoking status, alcohol consumption, income, and total energy, dietary intake of PUFA and omega-6 fatty acid was positively associated with DSST.

The DSST score increased about 0.06 standard deviation (SD) (about 1 score) with each SD increase in these fatty acids (8.8 g/d for PUFA and 7.9 g/d for omega-6) (P values were .02 for PUFA and .01 for omega-6).

However, it’s unclear what an improvement of 1 DSST score means clinically, said Dr. McIntyre. “The P value is significant, but how does that translate? Does this mean a person can now think more clearly or function better?”
 

‘Million dollar question’ remains unanswered

The fact that omega-6, considered neuroinflammatory, was associated with improved DSST score illustrates the complexity of this field, said Dr. McIntyre.

“We’re learning that when it comes to inflammation, many of the molecules in our brain that are implicated as anti-inflammatory can also be pro-inflammatory, so bad guys can be good guys and good guys can be bad guys.”

It speaks to the notion of homeostasis, he added. “Just like a seesaw; when you push this part down, that part goes up.”

The analysis showed the animal fluency score increased about 0.05 SD (around 0.3 score) with each SD (1.1 g/d) increase in dietary intake of omega-3.

There were no significant associations between other dietary fat intake and cognitive performance.

The researchers investigated the role of oxidative stress and antioxidant biomarkers (gamma glutamyl transpeptidase [GGT], bilirubin, uric acid, and vitamin D).

Cells produce oxidative radicals that are normally “mopped up” by our “innate antioxidant capability,” said Dr. McIntyre. “But in states of cognitive impairment, these oxidative stress markers accumulate and they exceed what the normal innate response is able to manage.”

The study showed GGT levels decreased with increased PUFA and omega-6 fatty acid intakes; levels of bilirubin decreased with increase in most dietary fat intakes; uric acid levels decreased with MUFA intake and omega-6/omega-3 ratio; and vitamin D levels increased with omega-3 fatty acid intake but decreased with SFAT intake.

Causal mediation analysis showed the association between dietary intake of fatty acids and DSST performance was partially mediated by GGT levels. However, Dr. McIntyre emphasized that this does not prove causality.

“The million dollar question is, is this the sole explanation for the association? In other words, is it the oxidative stress that caused the cognitive impairment and therefore correcting it improved it, or is it the case that oxidative stress is a proxy of other activities that are also taking place?”
 

A ‘plausible’ link

In an editorial, Candida Rebello, PhD, of the department of integrated physiology and molecular medicine at Pennington Biomedical Research Center, Baton Rouge, La., said the finding that omega-3 and omega-6 fatty acids are positively associated with cognition in older adults makes some sense.

She noted that aging is associated with an overt inflammatory phenotype, and evidence shows these fatty acids are precursors for bioactive molecules that play a role in self-limiting the acute inflammatory response.

Dr. Rebello said the positive association of omega-6 fatty acid with cognition shown in this study contrasts with the “common belief” that increasing dietary intake of these fatty acids enhances inflammation, but agreed the association is “plausible.”

She said it’s “essential” to determine “the underlying mechanisms that regulate the diverse features of inflammation and sort out the processes that protect from neuronal damage and those that contribute towards it.”

She noted the ratio of omega-6 to omega-3 is about 15:1 in the present day Western diet, as opposed to a 1:1 ratio in diets of the past. Omega-3 fatty acids are found in fish oil supplements and fatty fish like mackerel and salmon, while cereal, grains, and vegetable oil are sources of omega-6.

Attaining a measure of balance of fatty acids in the diet may be a “prudent approach,” said Dr. Rebello. “Substituting some meat entrées with fatty fish and polyunsaturated vegetable oils with monounsaturated fats such as olive oil are small changes that are likely to garner adherence.”

Dr. Rebello noted that the study used NHANES food intake data, which rely on participant self-report and so may not be accurate.

The study received funding from the MOE (Ministry of Education in China) Project of Humanities and Social Sciences and the Research Startup Fund of Southwest University. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, and AbbVie. He is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Dietary intake of polyunsaturated fatty acids (PUFA), particularly omega 6, is associated with improved cognitive function in older adults, new research suggests.

The study provides important “pieces of the puzzle” of the diet and cognition connection, but the results aren’t “ready for prime time,” study investigator Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“I don’t think we’re there yet when it comes to recommending supplementation to the general public,” said Dr. McIntyre, adding a larger “more compelling study” is needed.

The study was published online Jan. 14 in The American Journal of Geriatric Psychiatry.
 

Clinically meaningful?

Research shows that 25%-50% of community-dwelling adults aged 65-85 years have some cognitive impairment. Other evidence indicates cognition is affected by dietary fat intake.

Many lines of research show that alterations in lipid homeostasis can cause brain dysfunction, said Dr. McIntyre. “This shouldn’t surprise us because our brain is made up of protein, water, and fat.”

This new analysis used combined data from the 2011-2012 and 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES), a series of ongoing cross-sectional surveys conducted by the Centers for Disease Control and Prevention. The data are collected in two phases, an in-home face-to-face interview and a physical examination.

Researchers obtained dietary intake information through two 24-hour dietary recall interviews. Dietary information included total energy (kcal/d), intakes in grams per day (g/d) of total fat, saturated fatty acid (SFAT), monounsaturated fatty acid (MUFA), PUFA, total omega-3 and total omega-6 fatty acids, and milligrams per day (mg/d) of cholesterol.

For cognitive function, the researchers used total and delayed recall scores of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), the animal fluency test, and the digit symbol substitution test (DSST).

The study included 2,253 adults aged 60 years and older (mean age, 69.4 years) and 51% were non-Hispanic White individuals.

After adjustment for age, sex, race/ethnicity, educational attainment, smoking status, alcohol consumption, income, and total energy, dietary intake of PUFA and omega-6 fatty acid was positively associated with DSST.

The DSST score increased about 0.06 standard deviation (SD) (about 1 score) with each SD increase in these fatty acids (8.8 g/d for PUFA and 7.9 g/d for omega-6) (P values were .02 for PUFA and .01 for omega-6).

However, it’s unclear what an improvement of 1 DSST score means clinically, said Dr. McIntyre. “The P value is significant, but how does that translate? Does this mean a person can now think more clearly or function better?”
 

‘Million dollar question’ remains unanswered

The fact that omega-6, considered neuroinflammatory, was associated with improved DSST score illustrates the complexity of this field, said Dr. McIntyre.

“We’re learning that when it comes to inflammation, many of the molecules in our brain that are implicated as anti-inflammatory can also be pro-inflammatory, so bad guys can be good guys and good guys can be bad guys.”

It speaks to the notion of homeostasis, he added. “Just like a seesaw; when you push this part down, that part goes up.”

The analysis showed the animal fluency score increased about 0.05 SD (around 0.3 score) with each SD (1.1 g/d) increase in dietary intake of omega-3.

There were no significant associations between other dietary fat intake and cognitive performance.

The researchers investigated the role of oxidative stress and antioxidant biomarkers (gamma glutamyl transpeptidase [GGT], bilirubin, uric acid, and vitamin D).

Cells produce oxidative radicals that are normally “mopped up” by our “innate antioxidant capability,” said Dr. McIntyre. “But in states of cognitive impairment, these oxidative stress markers accumulate and they exceed what the normal innate response is able to manage.”

The study showed GGT levels decreased with increased PUFA and omega-6 fatty acid intakes; levels of bilirubin decreased with increase in most dietary fat intakes; uric acid levels decreased with MUFA intake and omega-6/omega-3 ratio; and vitamin D levels increased with omega-3 fatty acid intake but decreased with SFAT intake.

Causal mediation analysis showed the association between dietary intake of fatty acids and DSST performance was partially mediated by GGT levels. However, Dr. McIntyre emphasized that this does not prove causality.

“The million dollar question is, is this the sole explanation for the association? In other words, is it the oxidative stress that caused the cognitive impairment and therefore correcting it improved it, or is it the case that oxidative stress is a proxy of other activities that are also taking place?”
 

A ‘plausible’ link

In an editorial, Candida Rebello, PhD, of the department of integrated physiology and molecular medicine at Pennington Biomedical Research Center, Baton Rouge, La., said the finding that omega-3 and omega-6 fatty acids are positively associated with cognition in older adults makes some sense.

She noted that aging is associated with an overt inflammatory phenotype, and evidence shows these fatty acids are precursors for bioactive molecules that play a role in self-limiting the acute inflammatory response.

Dr. Rebello said the positive association of omega-6 fatty acid with cognition shown in this study contrasts with the “common belief” that increasing dietary intake of these fatty acids enhances inflammation, but agreed the association is “plausible.”

She said it’s “essential” to determine “the underlying mechanisms that regulate the diverse features of inflammation and sort out the processes that protect from neuronal damage and those that contribute towards it.”

She noted the ratio of omega-6 to omega-3 is about 15:1 in the present day Western diet, as opposed to a 1:1 ratio in diets of the past. Omega-3 fatty acids are found in fish oil supplements and fatty fish like mackerel and salmon, while cereal, grains, and vegetable oil are sources of omega-6.

Attaining a measure of balance of fatty acids in the diet may be a “prudent approach,” said Dr. Rebello. “Substituting some meat entrées with fatty fish and polyunsaturated vegetable oils with monounsaturated fats such as olive oil are small changes that are likely to garner adherence.”

Dr. Rebello noted that the study used NHANES food intake data, which rely on participant self-report and so may not be accurate.

The study received funding from the MOE (Ministry of Education in China) Project of Humanities and Social Sciences and the Research Startup Fund of Southwest University. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, and AbbVie. He is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

A version of this article first appeared on WebMD.com.

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

A version of this article first appeared on WebMD.com.

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

A version of this article first appeared on WebMD.com.

Oncologists were less likely than many other specialists to be named in malpractice suits during 2021, notes the latest Medscape Malpractice Report.

Over a third (39%) of oncologists who were surveyed said that they had been named in at least one malpractice suit, according to the Medscape Oncologist Malpractice Report 2021.

Jupiterimages/ThinkStock

This number is considerably lower than that reported by physicians across all specialties (51%), and it is also much lower than that reported by oncologists in past years. In the 2019 report, 54% of oncologists surveyed said they had been named in a malpractice suit, while in the 2017 report, the figure was 53%.

The dramatic decline in malpractice suits may have much to do with the COVID-19 pandemic, when oncology care was in a state of flux.

“Fewer people were seeking cancer care during the COVID pandemic, which might have impacted the number of lawsuits brought against oncologists,” says Paul Walker, a New York–based malpractice attorney at Walker Medical Law, who represents physicians and other healthcare professionals.

“Additionally, a fair number of people who died of COVID were also older,” he pointed out, and it is often older people who get cancer, so there were fewer older people who consulted an oncologist or were treated by one, he added.

However, the pandemic may be storing up trouble for future years. “Patient fears of contracting COVID-19 have led many to avoid seeking or resuming care, so delays in diagnosing new cancer cases could mean that more patients are diagnosed at a later stage of their disease, leading to potential adverse events and malpractice claims,” commented David L. Feldman, MD, MBA, chief medical officer of The Doctors Company Group.

This latest 2021 Medscape Malpractice Report was compiled from an online survey that included more than 4,300 physicians from 29 specialties. It included 106 oncologists. More than half of respondents (56%) had been in practice for more than 25 years, and 54% were aged 60 years or older. The survey was available from May 21 to August 28, 2021.

Similar to findings in previous years, complications from treatment/surgery were the most common reason for the lawsuits (31%). Failure to make a correct diagnosis or a delay in diagnosis was the second most common reason (23%), while 20% of patients sued because of a poor outcome or disease progression.
 

Surprise at being sued

Among the oncologists who reported involvement in a lawsuit in 2021, the majority (86%) said they were “very surprised” or “somewhat surprised” by the malpractice suit, which is similar to that of other physicians surveyed. However, fewer were surprised this year as compared to 2019 and 2017 (90% and 94%).

One reason for the surprise over the litigation was that it concerned a patient who had been treated a long time ago. One oncologist wrote that “the patient had not seen me for over 7 years and during that time, he did not call me with his new symptomatology. I was only named in the suit because I had previously been involved.”

Another common scenario reported by oncologists was being named in a lawsuit which was brought by another clinician’s patient. “I was the chairperson of the department, and one of the doctors in the practice was involved in the suit,” wrote one respondent. “I was named as an accomplice.”

More than half of surveyed oncologists said that they were able to identify the patient who bought the suit, and these figures are again comparable to those of other physicians. One oncologist commented that in the case he was involved with, the family did not understand or accept the nature of cancer and the different ways that a patient could die of complications. This patient had died of sepsis and pneumonia related to decubitus ulcers that were completely unrelated to her radiation therapy.

As in the case above, sometimes it is the family who filed the lawsuit, not the patient.

“The patient may even recognize that you did your best and be grateful for your skill and efforts, but the family can’t accept that grandma died of cancer and brings a lawsuit,” said Dennis Hursh, an attorney with Physicians Agreement Health Law in Pennsylvania.

When looking at outcomes of the lawsuit, 40% of oncologists were dismissed from the suit within the first few months, or the case was settled before going to trial. This trend is also consistent with the results from the 2019 and 2017 surveys. When the case did go to trial, 10% received a favorable verdict, which was the same in 2019.

“It seems that most of my clients end up being released from lawsuits, and many lawsuits are dismissed prior to proceeding to trial,” Mr. Hursh commented.
 

Murdering psychopath

Some oncologists weighed in on what they felt was the worst experience of being sued.

“Mental anguish, knowing that I did nothing wrong,” said one physician. Another reported that it was a feeling of being “inadequate and totally alone.”

Another oncologist commented that the “depositions from lawyers implied that I was worse than a murdering psychopath. My reputation was permanently damaged.”

However, the vast majority of oncologists (88%) did not believe that the lawsuit negatively affected their career, which was similar to physicians in general. That said, many did complain about the ongoing requirement to report the lawsuit to the credentialing committee, even if it was dismissed, and then having to pay increased malpractice premiums. “I still need to document this episode every single time I apply for any medical position, even more than 29 years after I was dismissed from the case,” said one respondent.

When asked if they would do anything differently, many oncologists (42%) said no, they would not have done anything differently. This is similar to the responses from physicians in general and with 2019 responses from oncologists. However, 15% of the respondents said that in retrospect, they would not have taken on that patient to begin with.

Some oncologists noted that they would have been more conscientious in relaying the information to the referring physician. Evan Lyman, an associate attorney at Voute, Lohrfink, McAndrew, Meisner & Roberts, LLP, in White Plains, N.Y., pointed out that a common reason for lawsuits is a slip-up of communication between the specialist and the referring physician.

Oncologists who had been sued have some insights to offer to colleagues, should they find themselves in a similar situation.

“Only answer with short and precise statements,” wrote one oncologist. “Attend all the depositions as much as you can; they are more likely to fabricate or exaggerate if you are not sitting in the room.”

Another physician said to base “everything on the medical record and do not answer hypothetical questions.”

“Document all interactions with patients as if a jury will be reading them, word by word,” said one respondent.

As for the public or patients, oncologists had this message: “malpractice suits should be rarely launched and only when gross errors can be absolutely proven.”

Another oncologist pointed out that communication is key. “Speak to the physicians against whom you have distrust. Lots of things could be cleared by good communication.”

A version of this article first appeared on Medscape.com.

Oncologists were less likely than many other specialists to be named in malpractice suits during 2021, notes the latest Medscape Malpractice Report.

Over a third (39%) of oncologists who were surveyed said that they had been named in at least one malpractice suit, according to the Medscape Oncologist Malpractice Report 2021.

Jupiterimages/ThinkStock

This number is considerably lower than that reported by physicians across all specialties (51%), and it is also much lower than that reported by oncologists in past years. In the 2019 report, 54% of oncologists surveyed said they had been named in a malpractice suit, while in the 2017 report, the figure was 53%.

The dramatic decline in malpractice suits may have much to do with the COVID-19 pandemic, when oncology care was in a state of flux.

“Fewer people were seeking cancer care during the COVID pandemic, which might have impacted the number of lawsuits brought against oncologists,” says Paul Walker, a New York–based malpractice attorney at Walker Medical Law, who represents physicians and other healthcare professionals.

“Additionally, a fair number of people who died of COVID were also older,” he pointed out, and it is often older people who get cancer, so there were fewer older people who consulted an oncologist or were treated by one, he added.

However, the pandemic may be storing up trouble for future years. “Patient fears of contracting COVID-19 have led many to avoid seeking or resuming care, so delays in diagnosing new cancer cases could mean that more patients are diagnosed at a later stage of their disease, leading to potential adverse events and malpractice claims,” commented David L. Feldman, MD, MBA, chief medical officer of The Doctors Company Group.

This latest 2021 Medscape Malpractice Report was compiled from an online survey that included more than 4,300 physicians from 29 specialties. It included 106 oncologists. More than half of respondents (56%) had been in practice for more than 25 years, and 54% were aged 60 years or older. The survey was available from May 21 to August 28, 2021.

Similar to findings in previous years, complications from treatment/surgery were the most common reason for the lawsuits (31%). Failure to make a correct diagnosis or a delay in diagnosis was the second most common reason (23%), while 20% of patients sued because of a poor outcome or disease progression.
 

Surprise at being sued

Among the oncologists who reported involvement in a lawsuit in 2021, the majority (86%) said they were “very surprised” or “somewhat surprised” by the malpractice suit, which is similar to that of other physicians surveyed. However, fewer were surprised this year as compared to 2019 and 2017 (90% and 94%).

One reason for the surprise over the litigation was that it concerned a patient who had been treated a long time ago. One oncologist wrote that “the patient had not seen me for over 7 years and during that time, he did not call me with his new symptomatology. I was only named in the suit because I had previously been involved.”

Another common scenario reported by oncologists was being named in a lawsuit which was brought by another clinician’s patient. “I was the chairperson of the department, and one of the doctors in the practice was involved in the suit,” wrote one respondent. “I was named as an accomplice.”

More than half of surveyed oncologists said that they were able to identify the patient who bought the suit, and these figures are again comparable to those of other physicians. One oncologist commented that in the case he was involved with, the family did not understand or accept the nature of cancer and the different ways that a patient could die of complications. This patient had died of sepsis and pneumonia related to decubitus ulcers that were completely unrelated to her radiation therapy.

As in the case above, sometimes it is the family who filed the lawsuit, not the patient.

“The patient may even recognize that you did your best and be grateful for your skill and efforts, but the family can’t accept that grandma died of cancer and brings a lawsuit,” said Dennis Hursh, an attorney with Physicians Agreement Health Law in Pennsylvania.

When looking at outcomes of the lawsuit, 40% of oncologists were dismissed from the suit within the first few months, or the case was settled before going to trial. This trend is also consistent with the results from the 2019 and 2017 surveys. When the case did go to trial, 10% received a favorable verdict, which was the same in 2019.

“It seems that most of my clients end up being released from lawsuits, and many lawsuits are dismissed prior to proceeding to trial,” Mr. Hursh commented.
 

Murdering psychopath

Some oncologists weighed in on what they felt was the worst experience of being sued.

“Mental anguish, knowing that I did nothing wrong,” said one physician. Another reported that it was a feeling of being “inadequate and totally alone.”

Another oncologist commented that the “depositions from lawyers implied that I was worse than a murdering psychopath. My reputation was permanently damaged.”

However, the vast majority of oncologists (88%) did not believe that the lawsuit negatively affected their career, which was similar to physicians in general. That said, many did complain about the ongoing requirement to report the lawsuit to the credentialing committee, even if it was dismissed, and then having to pay increased malpractice premiums. “I still need to document this episode every single time I apply for any medical position, even more than 29 years after I was dismissed from the case,” said one respondent.

When asked if they would do anything differently, many oncologists (42%) said no, they would not have done anything differently. This is similar to the responses from physicians in general and with 2019 responses from oncologists. However, 15% of the respondents said that in retrospect, they would not have taken on that patient to begin with.

Some oncologists noted that they would have been more conscientious in relaying the information to the referring physician. Evan Lyman, an associate attorney at Voute, Lohrfink, McAndrew, Meisner & Roberts, LLP, in White Plains, N.Y., pointed out that a common reason for lawsuits is a slip-up of communication between the specialist and the referring physician.

Oncologists who had been sued have some insights to offer to colleagues, should they find themselves in a similar situation.

“Only answer with short and precise statements,” wrote one oncologist. “Attend all the depositions as much as you can; they are more likely to fabricate or exaggerate if you are not sitting in the room.”

Another physician said to base “everything on the medical record and do not answer hypothetical questions.”

“Document all interactions with patients as if a jury will be reading them, word by word,” said one respondent.

As for the public or patients, oncologists had this message: “malpractice suits should be rarely launched and only when gross errors can be absolutely proven.”

Another oncologist pointed out that communication is key. “Speak to the physicians against whom you have distrust. Lots of things could be cleared by good communication.”

A version of this article first appeared on Medscape.com.

Oncologists were less likely than many other specialists to be named in malpractice suits during 2021, notes the latest Medscape Malpractice Report.

Over a third (39%) of oncologists who were surveyed said that they had been named in at least one malpractice suit, according to the Medscape Oncologist Malpractice Report 2021.

Jupiterimages/ThinkStock

This number is considerably lower than that reported by physicians across all specialties (51%), and it is also much lower than that reported by oncologists in past years. In the 2019 report, 54% of oncologists surveyed said they had been named in a malpractice suit, while in the 2017 report, the figure was 53%.

The dramatic decline in malpractice suits may have much to do with the COVID-19 pandemic, when oncology care was in a state of flux.

“Fewer people were seeking cancer care during the COVID pandemic, which might have impacted the number of lawsuits brought against oncologists,” says Paul Walker, a New York–based malpractice attorney at Walker Medical Law, who represents physicians and other healthcare professionals.

“Additionally, a fair number of people who died of COVID were also older,” he pointed out, and it is often older people who get cancer, so there were fewer older people who consulted an oncologist or were treated by one, he added.

However, the pandemic may be storing up trouble for future years. “Patient fears of contracting COVID-19 have led many to avoid seeking or resuming care, so delays in diagnosing new cancer cases could mean that more patients are diagnosed at a later stage of their disease, leading to potential adverse events and malpractice claims,” commented David L. Feldman, MD, MBA, chief medical officer of The Doctors Company Group.

This latest 2021 Medscape Malpractice Report was compiled from an online survey that included more than 4,300 physicians from 29 specialties. It included 106 oncologists. More than half of respondents (56%) had been in practice for more than 25 years, and 54% were aged 60 years or older. The survey was available from May 21 to August 28, 2021.

Similar to findings in previous years, complications from treatment/surgery were the most common reason for the lawsuits (31%). Failure to make a correct diagnosis or a delay in diagnosis was the second most common reason (23%), while 20% of patients sued because of a poor outcome or disease progression.
 

Surprise at being sued

Among the oncologists who reported involvement in a lawsuit in 2021, the majority (86%) said they were “very surprised” or “somewhat surprised” by the malpractice suit, which is similar to that of other physicians surveyed. However, fewer were surprised this year as compared to 2019 and 2017 (90% and 94%).

One reason for the surprise over the litigation was that it concerned a patient who had been treated a long time ago. One oncologist wrote that “the patient had not seen me for over 7 years and during that time, he did not call me with his new symptomatology. I was only named in the suit because I had previously been involved.”

Another common scenario reported by oncologists was being named in a lawsuit which was brought by another clinician’s patient. “I was the chairperson of the department, and one of the doctors in the practice was involved in the suit,” wrote one respondent. “I was named as an accomplice.”

More than half of surveyed oncologists said that they were able to identify the patient who bought the suit, and these figures are again comparable to those of other physicians. One oncologist commented that in the case he was involved with, the family did not understand or accept the nature of cancer and the different ways that a patient could die of complications. This patient had died of sepsis and pneumonia related to decubitus ulcers that were completely unrelated to her radiation therapy.

As in the case above, sometimes it is the family who filed the lawsuit, not the patient.

“The patient may even recognize that you did your best and be grateful for your skill and efforts, but the family can’t accept that grandma died of cancer and brings a lawsuit,” said Dennis Hursh, an attorney with Physicians Agreement Health Law in Pennsylvania.

When looking at outcomes of the lawsuit, 40% of oncologists were dismissed from the suit within the first few months, or the case was settled before going to trial. This trend is also consistent with the results from the 2019 and 2017 surveys. When the case did go to trial, 10% received a favorable verdict, which was the same in 2019.

“It seems that most of my clients end up being released from lawsuits, and many lawsuits are dismissed prior to proceeding to trial,” Mr. Hursh commented.
 

Murdering psychopath

Some oncologists weighed in on what they felt was the worst experience of being sued.

“Mental anguish, knowing that I did nothing wrong,” said one physician. Another reported that it was a feeling of being “inadequate and totally alone.”

Another oncologist commented that the “depositions from lawyers implied that I was worse than a murdering psychopath. My reputation was permanently damaged.”

However, the vast majority of oncologists (88%) did not believe that the lawsuit negatively affected their career, which was similar to physicians in general. That said, many did complain about the ongoing requirement to report the lawsuit to the credentialing committee, even if it was dismissed, and then having to pay increased malpractice premiums. “I still need to document this episode every single time I apply for any medical position, even more than 29 years after I was dismissed from the case,” said one respondent.

When asked if they would do anything differently, many oncologists (42%) said no, they would not have done anything differently. This is similar to the responses from physicians in general and with 2019 responses from oncologists. However, 15% of the respondents said that in retrospect, they would not have taken on that patient to begin with.

Some oncologists noted that they would have been more conscientious in relaying the information to the referring physician. Evan Lyman, an associate attorney at Voute, Lohrfink, McAndrew, Meisner & Roberts, LLP, in White Plains, N.Y., pointed out that a common reason for lawsuits is a slip-up of communication between the specialist and the referring physician.

Oncologists who had been sued have some insights to offer to colleagues, should they find themselves in a similar situation.

“Only answer with short and precise statements,” wrote one oncologist. “Attend all the depositions as much as you can; they are more likely to fabricate or exaggerate if you are not sitting in the room.”

Another physician said to base “everything on the medical record and do not answer hypothetical questions.”

“Document all interactions with patients as if a jury will be reading them, word by word,” said one respondent.

As for the public or patients, oncologists had this message: “malpractice suits should be rarely launched and only when gross errors can be absolutely proven.”

Another oncologist pointed out that communication is key. “Speak to the physicians against whom you have distrust. Lots of things could be cleared by good communication.”

A version of this article first appeared on Medscape.com.

Cerebral palsy (CP) embodies a collection of disorders involving permanent but nonprogressive motor dysfunction secondary to one of a variety of abnormal disturbances that can occur in the developing fetal or infantile brain.¹ The motor impairment of CP classically leads to irregularities in muscle tone, posture, and/or movement, resulting in limitations of functional abilities that vary in severity.^1,2 Patients with CP commonly experience dysphagia, gastroesophageal reflux disease, impaired airway clearance, chest wall and spine deformities, restrictive lung disease, and/or recurrent aspiration.¹ Consequently, pulmonary disease is the leading cause of morbidity and mortality in patients with severe CP, characterized by recurrent bacterial infections.^3,4

Frequent antibiotic use increases the risk of multidrug-resistant pathogen formation and hypersensitivity to antibiotics. Life-threatening allergic reactions in a patient population with impaired lung function significantly complicates patient management, often leading to suboptimal treatment with second-line agents.⁵ This case study describes a previously penicillin-tolerant patient with CP who developed a type I hypersensitivity reaction to ceftazidime/avibactam and was treated successfully with the antibiotic after rapid induction of temporary tolerance.

Case Presentation

A 34-year-old male with a complex medical history of severe spastic CP and atonic seizures was recently diagnosed with adenocarcinoma of the colon and admitted for ileostomy and sigmoidectomy. The surgery was complicated by spillage of intestinal contents into the peritoneal cavity 3 days postoperation. The patient was urgently taken to the operating room for exploratory laparotomy, culminating in remaining colectomy, complete abdominal washout, and wound vacuum placement. He continued to deteriorate clinically over the next few weeks, beginning with the development of feculent peritonitis and septic shock. Respiratory distress ensued, and the patient required a tracheostomy with mechanical ventilation. A computed tomography of the chest was consistent with multifocal pneumonia, and a respiratory culture of bronchioalveolar lavage fluid cultivated Klebsiella pneumoniae, a carbapenem-resistant Enterobacteriaceae.

The infectious disease service was consulted and recommended ceftazidime/avibactam as the only acceptable antibiotic to treat this organism. The patient had no history of drug hypersensitivities. However, he developed diffuse, generalized urticaria and predominately right-sided flushing immediately following the onset of the antibiotic infusion. The urticaria was pruritic. The patient did not have angioedema, and he did not experience any adverse respiratory, cardiac, gastrointestinal, or neurologic symptoms. The infusion was ceased immediately, and the patient was treated with a combination of diphenhydramine 50 mg IV and ranitidine 50 mg IV. Resolution of his hypersensitivity symptoms occurred within an hour of treatment, and vital signs remained stable with no resurgence of symptoms. At the time of his reaction, the patient also was taking pantoprazole, valproate, metoprolol, risperidone, and oxycodone as needed for pain. A tryptase level was not measured.

Discussion

This is the first reported case in the literature to describe a type I hypersensitivity reaction with rapid IV induction of tolerance to ceftazidime/avibactam. We describe his reaction as type I hypersensitivity because the patient developed immediate generalized urticaria and flushing. Use of a safe desensitization protocol, demonstrated in this case report, is paramount to optimal management of infections in patient populations with severely decreased lung function, such as CP.^5-7 It provides a safe and effective technique to maintain patients on first line, preferred therapy, despite their increased risk of potentially life-threatening allergic reactions.

Interestingly, this patient previously tolerated penicillins and cephalosporins without adverse reactions, suggesting the possibility of a non–IgE-mediated vs an IgE-mediated mechanism to the hypersensitivity reaction. The patient also was receiving oxycodone at the time of his reaction, and oxycodone can cause nonspecific mast cell degranulation. Additional information from skin testing to ceftazidime/avibactam could help determine whether the patient had an IgE-mediated hypersensitivity reaction. This information could help clarify the culprit agent and guide further avoidance recommendations.

Unfortunately, because the patient was critically ill, skin testing was not performed, and he underwent an urgent antibiotic desensitization with success. It was recommended that the patient follow up in the allergy and immunology clinic for further evaluation with skin testing to ceftazidime/avibactam as well as other β-lactams to determine his future risk of reaction. Unfortunately, he was lost to follow-up.

Frequent IV antibiotic use is a risk factor for the development of antibiotic allergies.^8,9 This patient had received many prior courses of IV antibiotics, and this factor most likely contributed to his immediate hypersensitivity reaction to ceftazidime/avibactam. Fortunately, he tolerated a rapid induction of tolerance.

As life expectancies for patients with chronic medical conditions that involve recurrent infections increase, the associated emergence of multidrug-resistant pathogens and necessity for use of novel combination antibiotics should prompt further investigation of nonirritating doses of these drugs for skin testing in the case of drug hypersensitivities. This information would be essential for skin prick testing and determination of whether patients have a true IgE-mediated reaction to these antibiotics.

Conclusions

This is the first case report demonstrating a successful rapid induction of tolerance for the antibiotic ceftazidime/avibactam. Fortunately, the patient tolerated the desensitization procedure without further adverse reactions, and he had a resolution of his infection.

Cerebral palsy (CP) embodies a collection of disorders involving permanent but nonprogressive motor dysfunction secondary to one of a variety of abnormal disturbances that can occur in the developing fetal or infantile brain.¹ The motor impairment of CP classically leads to irregularities in muscle tone, posture, and/or movement, resulting in limitations of functional abilities that vary in severity.^1,2 Patients with CP commonly experience dysphagia, gastroesophageal reflux disease, impaired airway clearance, chest wall and spine deformities, restrictive lung disease, and/or recurrent aspiration.¹ Consequently, pulmonary disease is the leading cause of morbidity and mortality in patients with severe CP, characterized by recurrent bacterial infections.^3,4

Frequent antibiotic use increases the risk of multidrug-resistant pathogen formation and hypersensitivity to antibiotics. Life-threatening allergic reactions in a patient population with impaired lung function significantly complicates patient management, often leading to suboptimal treatment with second-line agents.⁵ This case study describes a previously penicillin-tolerant patient with CP who developed a type I hypersensitivity reaction to ceftazidime/avibactam and was treated successfully with the antibiotic after rapid induction of temporary tolerance.

Case Presentation

A 34-year-old male with a complex medical history of severe spastic CP and atonic seizures was recently diagnosed with adenocarcinoma of the colon and admitted for ileostomy and sigmoidectomy. The surgery was complicated by spillage of intestinal contents into the peritoneal cavity 3 days postoperation. The patient was urgently taken to the operating room for exploratory laparotomy, culminating in remaining colectomy, complete abdominal washout, and wound vacuum placement. He continued to deteriorate clinically over the next few weeks, beginning with the development of feculent peritonitis and septic shock. Respiratory distress ensued, and the patient required a tracheostomy with mechanical ventilation. A computed tomography of the chest was consistent with multifocal pneumonia, and a respiratory culture of bronchioalveolar lavage fluid cultivated Klebsiella pneumoniae, a carbapenem-resistant Enterobacteriaceae.

The infectious disease service was consulted and recommended ceftazidime/avibactam as the only acceptable antibiotic to treat this organism. The patient had no history of drug hypersensitivities. However, he developed diffuse, generalized urticaria and predominately right-sided flushing immediately following the onset of the antibiotic infusion. The urticaria was pruritic. The patient did not have angioedema, and he did not experience any adverse respiratory, cardiac, gastrointestinal, or neurologic symptoms. The infusion was ceased immediately, and the patient was treated with a combination of diphenhydramine 50 mg IV and ranitidine 50 mg IV. Resolution of his hypersensitivity symptoms occurred within an hour of treatment, and vital signs remained stable with no resurgence of symptoms. At the time of his reaction, the patient also was taking pantoprazole, valproate, metoprolol, risperidone, and oxycodone as needed for pain. A tryptase level was not measured.

Discussion

This is the first reported case in the literature to describe a type I hypersensitivity reaction with rapid IV induction of tolerance to ceftazidime/avibactam. We describe his reaction as type I hypersensitivity because the patient developed immediate generalized urticaria and flushing. Use of a safe desensitization protocol, demonstrated in this case report, is paramount to optimal management of infections in patient populations with severely decreased lung function, such as CP.^5-7 It provides a safe and effective technique to maintain patients on first line, preferred therapy, despite their increased risk of potentially life-threatening allergic reactions.

Interestingly, this patient previously tolerated penicillins and cephalosporins without adverse reactions, suggesting the possibility of a non–IgE-mediated vs an IgE-mediated mechanism to the hypersensitivity reaction. The patient also was receiving oxycodone at the time of his reaction, and oxycodone can cause nonspecific mast cell degranulation. Additional information from skin testing to ceftazidime/avibactam could help determine whether the patient had an IgE-mediated hypersensitivity reaction. This information could help clarify the culprit agent and guide further avoidance recommendations.

Unfortunately, because the patient was critically ill, skin testing was not performed, and he underwent an urgent antibiotic desensitization with success. It was recommended that the patient follow up in the allergy and immunology clinic for further evaluation with skin testing to ceftazidime/avibactam as well as other β-lactams to determine his future risk of reaction. Unfortunately, he was lost to follow-up.

Frequent IV antibiotic use is a risk factor for the development of antibiotic allergies.^8,9 This patient had received many prior courses of IV antibiotics, and this factor most likely contributed to his immediate hypersensitivity reaction to ceftazidime/avibactam. Fortunately, he tolerated a rapid induction of tolerance.

As life expectancies for patients with chronic medical conditions that involve recurrent infections increase, the associated emergence of multidrug-resistant pathogens and necessity for use of novel combination antibiotics should prompt further investigation of nonirritating doses of these drugs for skin testing in the case of drug hypersensitivities. This information would be essential for skin prick testing and determination of whether patients have a true IgE-mediated reaction to these antibiotics.

Conclusions

This is the first case report demonstrating a successful rapid induction of tolerance for the antibiotic ceftazidime/avibactam. Fortunately, the patient tolerated the desensitization procedure without further adverse reactions, and he had a resolution of his infection.

Cerebral palsy (CP) embodies a collection of disorders involving permanent but nonprogressive motor dysfunction secondary to one of a variety of abnormal disturbances that can occur in the developing fetal or infantile brain.¹ The motor impairment of CP classically leads to irregularities in muscle tone, posture, and/or movement, resulting in limitations of functional abilities that vary in severity.^1,2 Patients with CP commonly experience dysphagia, gastroesophageal reflux disease, impaired airway clearance, chest wall and spine deformities, restrictive lung disease, and/or recurrent aspiration.¹ Consequently, pulmonary disease is the leading cause of morbidity and mortality in patients with severe CP, characterized by recurrent bacterial infections.^3,4

Frequent antibiotic use increases the risk of multidrug-resistant pathogen formation and hypersensitivity to antibiotics. Life-threatening allergic reactions in a patient population with impaired lung function significantly complicates patient management, often leading to suboptimal treatment with second-line agents.⁵ This case study describes a previously penicillin-tolerant patient with CP who developed a type I hypersensitivity reaction to ceftazidime/avibactam and was treated successfully with the antibiotic after rapid induction of temporary tolerance.

Case Presentation

A 34-year-old male with a complex medical history of severe spastic CP and atonic seizures was recently diagnosed with adenocarcinoma of the colon and admitted for ileostomy and sigmoidectomy. The surgery was complicated by spillage of intestinal contents into the peritoneal cavity 3 days postoperation. The patient was urgently taken to the operating room for exploratory laparotomy, culminating in remaining colectomy, complete abdominal washout, and wound vacuum placement. He continued to deteriorate clinically over the next few weeks, beginning with the development of feculent peritonitis and septic shock. Respiratory distress ensued, and the patient required a tracheostomy with mechanical ventilation. A computed tomography of the chest was consistent with multifocal pneumonia, and a respiratory culture of bronchioalveolar lavage fluid cultivated Klebsiella pneumoniae, a carbapenem-resistant Enterobacteriaceae.

The infectious disease service was consulted and recommended ceftazidime/avibactam as the only acceptable antibiotic to treat this organism. The patient had no history of drug hypersensitivities. However, he developed diffuse, generalized urticaria and predominately right-sided flushing immediately following the onset of the antibiotic infusion. The urticaria was pruritic. The patient did not have angioedema, and he did not experience any adverse respiratory, cardiac, gastrointestinal, or neurologic symptoms. The infusion was ceased immediately, and the patient was treated with a combination of diphenhydramine 50 mg IV and ranitidine 50 mg IV. Resolution of his hypersensitivity symptoms occurred within an hour of treatment, and vital signs remained stable with no resurgence of symptoms. At the time of his reaction, the patient also was taking pantoprazole, valproate, metoprolol, risperidone, and oxycodone as needed for pain. A tryptase level was not measured.

Discussion

This is the first reported case in the literature to describe a type I hypersensitivity reaction with rapid IV induction of tolerance to ceftazidime/avibactam. We describe his reaction as type I hypersensitivity because the patient developed immediate generalized urticaria and flushing. Use of a safe desensitization protocol, demonstrated in this case report, is paramount to optimal management of infections in patient populations with severely decreased lung function, such as CP.^5-7 It provides a safe and effective technique to maintain patients on first line, preferred therapy, despite their increased risk of potentially life-threatening allergic reactions.

Interestingly, this patient previously tolerated penicillins and cephalosporins without adverse reactions, suggesting the possibility of a non–IgE-mediated vs an IgE-mediated mechanism to the hypersensitivity reaction. The patient also was receiving oxycodone at the time of his reaction, and oxycodone can cause nonspecific mast cell degranulation. Additional information from skin testing to ceftazidime/avibactam could help determine whether the patient had an IgE-mediated hypersensitivity reaction. This information could help clarify the culprit agent and guide further avoidance recommendations.

Unfortunately, because the patient was critically ill, skin testing was not performed, and he underwent an urgent antibiotic desensitization with success. It was recommended that the patient follow up in the allergy and immunology clinic for further evaluation with skin testing to ceftazidime/avibactam as well as other β-lactams to determine his future risk of reaction. Unfortunately, he was lost to follow-up.

Frequent IV antibiotic use is a risk factor for the development of antibiotic allergies.^8,9 This patient had received many prior courses of IV antibiotics, and this factor most likely contributed to his immediate hypersensitivity reaction to ceftazidime/avibactam. Fortunately, he tolerated a rapid induction of tolerance.

As life expectancies for patients with chronic medical conditions that involve recurrent infections increase, the associated emergence of multidrug-resistant pathogens and necessity for use of novel combination antibiotics should prompt further investigation of nonirritating doses of these drugs for skin testing in the case of drug hypersensitivities. This information would be essential for skin prick testing and determination of whether patients have a true IgE-mediated reaction to these antibiotics.

Conclusions

This is the first case report demonstrating a successful rapid induction of tolerance for the antibiotic ceftazidime/avibactam. Fortunately, the patient tolerated the desensitization procedure without further adverse reactions, and he had a resolution of his infection.

As rheumatologists contend with vaccine hesitancy among certain subsets of patients, the American College of Rheumatology has released updated clinical guidelines on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases (RMDs), including new recommendations on supplemental and booster doses.

The revised guidance from this fifth version of the ACR guidelines includes strongly recommending that all RMD patients receive a booster after their primary vaccine series, regardless of whether they have been naturally infected with COVID-19. In addition, they strongly recommend third supplemental doses for patients with autoimmune inflammatory rheumatic diseases (AIIRDs) who likely mounted an inadequate vaccine response, which would then be followed by a fourth booster dose as advised by the Centers for Disease Control and Prevention for immunocompromised individuals.

South_agency/Getty Images

Other recommendations include pre-exposure prophylaxis monoclonal antibody treatment for high-risk AIIRD patients, defined as those with moderate to severely compromised immune systems who may not mount an adequate immune response to COVID-19 vaccination, when it is available and authorized for emergency use by the Food and Drug Administration, as well as monoclonal antibody therapy for postexposure prophylaxis of asymptomatic, recently exposed high-risk AIIRD patients or as treatment for newly symptomatic, high-risk AIIRD patients. The ACR guidance notes that, currently, neither the monoclonal antibodies bamlanivimab and etesevimab (administered together) nor casirivimab and imdevimab (REGEN-COV), are licensed or available under an emergency use authorization given their lack of activity against the Omicron variant, the dominant strain of SARS-CoV-2 circulating in the United States.

Finally, the guidance clarified that the timing of intravenous immunoglobulin doses does not need to be modified around the administration of COVID vaccine doses, based on moderate consensus among task force members.

Vaccine hesitancy in community rheumatology practices

The revised guidelines were released just as Arthritis & Rheumatology published a new study that assessed vaccine hesitancy among rheumatology patients on immunomodulatory therapies. A three-item electronic survey was conducted at 101 offices within a community practice–based rheumatology research network and ultimately collected responses from 58,529 patients, 20,987 of whom had an AIIRD and were receiving targeted therapies like biologics or Janus kinase inhibitors.

Of the total respondents, 77% (n = 43,675) had been vaccinated, 16.9% were not vaccinated and did not plan to be, and 6.1% were not vaccinated but planned to be. However, AIIRD patients were 16% less likely to be vaccinated, compared with the other patients, such as those with osteoarthritis or osteoporosis who were not receiving disease-modifying antirheumatic drugs (76.9% vs. 87%; odds ratio, 0.84; 95% confidence interval, 0.77-0.92; P < .001). Multivariable analysis also found that older patients (OR, 1.49 per 10 years) and Asians (OR, 2.42; 95% CI, 1.77-3.33) were more likely to be vaccinated.

Courtesy UAB Photo

“Rheumatologists need to be asking their patients more than just: ‘Are you vaccinated?’ ” Jeffrey Curtis, MD, MPH, head of the ACR COVID-19 vaccine task force and a coauthor of the vaccine hesitancy study, said in an interview. “A year ago, that was a fine approach, but now they need to be asking whether you’ve been vaccinated, and with what, and how many times, and how recently. There are a whole lot of subtleties there; ‘vaccinated: yes or no’ is just the tip of the iceberg.”

His research into the vaccine hesitant includes recent anecdotal data from thousands of patients treated in local rheumatology community practices, many of whom cited long-term safety data and potential side effects as reasons why they were unwilling to get vaccinated. But despite their on-paper responses, he cautioned rheumatologists to think critically when determining which patients may truly be open to vaccination.

“If you’re designing strategies to affect vaccine hesitancy, you may be wasting your time with some people,” said Dr. Curtis, professor of medicine at the University of Alabama at Birmingham. “A critical need is to figure out who are the patients who may be amendable to more information or an intervention or a little bit more time and care, and who are the people where you know, this is a lost cause: You don’t get a flu shot, you haven’t been vaccinated for shingles, [and] you’re not going to get this one either.

“In terms of a research agenda, how do we develop efficient, simple, short screening tools?” he added. “Something with a few helpful questions, on a patient portal or an iPad, that will do a good job identifying your patients at risk who haven’t had vaccination but that you might be able to spend time with, intervene, and actually change their mind. If you spend gobs of time with everyone, you’ll help some people, but clinicians don’t have an infinite amount of time.”

One of the authors of the vaccine hesitancy study acknowledged being employed by the rheumatology research network that hosted the survey. Several others, including Dr. Curtis, reported receiving grants and consulting fees from various pharmaceutical companies.

As rheumatologists contend with vaccine hesitancy among certain subsets of patients, the American College of Rheumatology has released updated clinical guidelines on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases (RMDs), including new recommendations on supplemental and booster doses.

The revised guidance from this fifth version of the ACR guidelines includes strongly recommending that all RMD patients receive a booster after their primary vaccine series, regardless of whether they have been naturally infected with COVID-19. In addition, they strongly recommend third supplemental doses for patients with autoimmune inflammatory rheumatic diseases (AIIRDs) who likely mounted an inadequate vaccine response, which would then be followed by a fourth booster dose as advised by the Centers for Disease Control and Prevention for immunocompromised individuals.

South_agency/Getty Images

Other recommendations include pre-exposure prophylaxis monoclonal antibody treatment for high-risk AIIRD patients, defined as those with moderate to severely compromised immune systems who may not mount an adequate immune response to COVID-19 vaccination, when it is available and authorized for emergency use by the Food and Drug Administration, as well as monoclonal antibody therapy for postexposure prophylaxis of asymptomatic, recently exposed high-risk AIIRD patients or as treatment for newly symptomatic, high-risk AIIRD patients. The ACR guidance notes that, currently, neither the monoclonal antibodies bamlanivimab and etesevimab (administered together) nor casirivimab and imdevimab (REGEN-COV), are licensed or available under an emergency use authorization given their lack of activity against the Omicron variant, the dominant strain of SARS-CoV-2 circulating in the United States.

Finally, the guidance clarified that the timing of intravenous immunoglobulin doses does not need to be modified around the administration of COVID vaccine doses, based on moderate consensus among task force members.

Vaccine hesitancy in community rheumatology practices

The revised guidelines were released just as Arthritis & Rheumatology published a new study that assessed vaccine hesitancy among rheumatology patients on immunomodulatory therapies. A three-item electronic survey was conducted at 101 offices within a community practice–based rheumatology research network and ultimately collected responses from 58,529 patients, 20,987 of whom had an AIIRD and were receiving targeted therapies like biologics or Janus kinase inhibitors.

Of the total respondents, 77% (n = 43,675) had been vaccinated, 16.9% were not vaccinated and did not plan to be, and 6.1% were not vaccinated but planned to be. However, AIIRD patients were 16% less likely to be vaccinated, compared with the other patients, such as those with osteoarthritis or osteoporosis who were not receiving disease-modifying antirheumatic drugs (76.9% vs. 87%; odds ratio, 0.84; 95% confidence interval, 0.77-0.92; P < .001). Multivariable analysis also found that older patients (OR, 1.49 per 10 years) and Asians (OR, 2.42; 95% CI, 1.77-3.33) were more likely to be vaccinated.

Courtesy UAB Photo

“Rheumatologists need to be asking their patients more than just: ‘Are you vaccinated?’ ” Jeffrey Curtis, MD, MPH, head of the ACR COVID-19 vaccine task force and a coauthor of the vaccine hesitancy study, said in an interview. “A year ago, that was a fine approach, but now they need to be asking whether you’ve been vaccinated, and with what, and how many times, and how recently. There are a whole lot of subtleties there; ‘vaccinated: yes or no’ is just the tip of the iceberg.”

His research into the vaccine hesitant includes recent anecdotal data from thousands of patients treated in local rheumatology community practices, many of whom cited long-term safety data and potential side effects as reasons why they were unwilling to get vaccinated. But despite their on-paper responses, he cautioned rheumatologists to think critically when determining which patients may truly be open to vaccination.

“If you’re designing strategies to affect vaccine hesitancy, you may be wasting your time with some people,” said Dr. Curtis, professor of medicine at the University of Alabama at Birmingham. “A critical need is to figure out who are the patients who may be amendable to more information or an intervention or a little bit more time and care, and who are the people where you know, this is a lost cause: You don’t get a flu shot, you haven’t been vaccinated for shingles, [and] you’re not going to get this one either.

“In terms of a research agenda, how do we develop efficient, simple, short screening tools?” he added. “Something with a few helpful questions, on a patient portal or an iPad, that will do a good job identifying your patients at risk who haven’t had vaccination but that you might be able to spend time with, intervene, and actually change their mind. If you spend gobs of time with everyone, you’ll help some people, but clinicians don’t have an infinite amount of time.”

One of the authors of the vaccine hesitancy study acknowledged being employed by the rheumatology research network that hosted the survey. Several others, including Dr. Curtis, reported receiving grants and consulting fees from various pharmaceutical companies.

As rheumatologists contend with vaccine hesitancy among certain subsets of patients, the American College of Rheumatology has released updated clinical guidelines on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases (RMDs), including new recommendations on supplemental and booster doses.

The revised guidance from this fifth version of the ACR guidelines includes strongly recommending that all RMD patients receive a booster after their primary vaccine series, regardless of whether they have been naturally infected with COVID-19. In addition, they strongly recommend third supplemental doses for patients with autoimmune inflammatory rheumatic diseases (AIIRDs) who likely mounted an inadequate vaccine response, which would then be followed by a fourth booster dose as advised by the Centers for Disease Control and Prevention for immunocompromised individuals.

South_agency/Getty Images

Other recommendations include pre-exposure prophylaxis monoclonal antibody treatment for high-risk AIIRD patients, defined as those with moderate to severely compromised immune systems who may not mount an adequate immune response to COVID-19 vaccination, when it is available and authorized for emergency use by the Food and Drug Administration, as well as monoclonal antibody therapy for postexposure prophylaxis of asymptomatic, recently exposed high-risk AIIRD patients or as treatment for newly symptomatic, high-risk AIIRD patients. The ACR guidance notes that, currently, neither the monoclonal antibodies bamlanivimab and etesevimab (administered together) nor casirivimab and imdevimab (REGEN-COV), are licensed or available under an emergency use authorization given their lack of activity against the Omicron variant, the dominant strain of SARS-CoV-2 circulating in the United States.

Finally, the guidance clarified that the timing of intravenous immunoglobulin doses does not need to be modified around the administration of COVID vaccine doses, based on moderate consensus among task force members.

Vaccine hesitancy in community rheumatology practices

The revised guidelines were released just as Arthritis & Rheumatology published a new study that assessed vaccine hesitancy among rheumatology patients on immunomodulatory therapies. A three-item electronic survey was conducted at 101 offices within a community practice–based rheumatology research network and ultimately collected responses from 58,529 patients, 20,987 of whom had an AIIRD and were receiving targeted therapies like biologics or Janus kinase inhibitors.

Of the total respondents, 77% (n = 43,675) had been vaccinated, 16.9% were not vaccinated and did not plan to be, and 6.1% were not vaccinated but planned to be. However, AIIRD patients were 16% less likely to be vaccinated, compared with the other patients, such as those with osteoarthritis or osteoporosis who were not receiving disease-modifying antirheumatic drugs (76.9% vs. 87%; odds ratio, 0.84; 95% confidence interval, 0.77-0.92; P < .001). Multivariable analysis also found that older patients (OR, 1.49 per 10 years) and Asians (OR, 2.42; 95% CI, 1.77-3.33) were more likely to be vaccinated.

Courtesy UAB Photo

“Rheumatologists need to be asking their patients more than just: ‘Are you vaccinated?’ ” Jeffrey Curtis, MD, MPH, head of the ACR COVID-19 vaccine task force and a coauthor of the vaccine hesitancy study, said in an interview. “A year ago, that was a fine approach, but now they need to be asking whether you’ve been vaccinated, and with what, and how many times, and how recently. There are a whole lot of subtleties there; ‘vaccinated: yes or no’ is just the tip of the iceberg.”

His research into the vaccine hesitant includes recent anecdotal data from thousands of patients treated in local rheumatology community practices, many of whom cited long-term safety data and potential side effects as reasons why they were unwilling to get vaccinated. But despite their on-paper responses, he cautioned rheumatologists to think critically when determining which patients may truly be open to vaccination.

“If you’re designing strategies to affect vaccine hesitancy, you may be wasting your time with some people,” said Dr. Curtis, professor of medicine at the University of Alabama at Birmingham. “A critical need is to figure out who are the patients who may be amendable to more information or an intervention or a little bit more time and care, and who are the people where you know, this is a lost cause: You don’t get a flu shot, you haven’t been vaccinated for shingles, [and] you’re not going to get this one either.

“In terms of a research agenda, how do we develop efficient, simple, short screening tools?” he added. “Something with a few helpful questions, on a patient portal or an iPad, that will do a good job identifying your patients at risk who haven’t had vaccination but that you might be able to spend time with, intervene, and actually change their mind. If you spend gobs of time with everyone, you’ll help some people, but clinicians don’t have an infinite amount of time.”

One of the authors of the vaccine hesitancy study acknowledged being employed by the rheumatology research network that hosted the survey. Several others, including Dr. Curtis, reported receiving grants and consulting fees from various pharmaceutical companies.

The Food and Drug Administration announced on Feb. 3 its investigation into “a possible increased risk of death” associated with the lymphoma drug umbralisib (Ukoniq).

The FDA granted accelerated approval to umbralisib in February 2021 for patients with two types of lymphoma: Adults with relapsed or refractory marginal zone lymphoma who received at least one prior therapy, and those with relapsed or refractory follicular lymphoma who received at least three prior therapies.

According to the FDA, the possible increased risk of death arose from early findings in a phase 3 trial evaluating the drug in a related type of cancer: chronic lymphocytic leukemia.

“Because of the seriousness of this safety concern and the similarities between the two types of cancer for which this drug is approved and the type of cancer that was studied in the clinical trial, we are alerting patients and health care professionals that we are reevaluating this risk against the benefits of Ukoniq [umbralisib] for its approved uses,” the FDA safety communication states.

The FDA said it performed an initial review of data from the phase 3, randomized controlled UNITY trial, which is evaluating the efficacy of umbralisib plus a monoclonal antibody in patients with chronic lymphocytic leukemia.

“The results showed a possible increased risk of death in patients receiving the combination of Ukoniq [umbralisib] and the monoclonal antibody compared to the control arm,” according to the FDA. “Those receiving the combination of Ukoniq [umbralisib] and the monoclonal antibody also experienced more serious adverse events than those in the control arm.”

Although the drug has not been approved for patients with chronic lymphocytic leukemia, the FDA believes the findings could “have implications for its approved uses” in marginal zone lymphoma and follicular lymphoma.

However, the phase 2 trial that led to February 2021 approvals found the drug’s safety profile to be “manageable,” with serious adverse reactions reported in 18% of patients receiving the dual oral inhibitor of phosphoinositide 3 kinase delta and casein kinase 1 epsilon. These adverse reactions included diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%); however, no elevated risk of death was indicated in that analysis.

The FDA noted it will continue to evaluate the results from the phase 3 UNITY trial in chronic lymphocytic leukemia and has suspended enrollment of new patients in other ongoing clinical trials of the drug.

The FDA stated that it would communicate its “final conclusions and recommendations when we have completed our review.” In the meantime, the agency asks health care professionals to review how patients receiving umbralisib are faring and discuss “the risks and benefits of continuing” versus switching to other treatments.

The FDA also asks clinicians and patients to report side effects involving the drug to the FDA MedWatch program.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration announced on Feb. 3 its investigation into “a possible increased risk of death” associated with the lymphoma drug umbralisib (Ukoniq).

The FDA granted accelerated approval to umbralisib in February 2021 for patients with two types of lymphoma: Adults with relapsed or refractory marginal zone lymphoma who received at least one prior therapy, and those with relapsed or refractory follicular lymphoma who received at least three prior therapies.

According to the FDA, the possible increased risk of death arose from early findings in a phase 3 trial evaluating the drug in a related type of cancer: chronic lymphocytic leukemia.

“Because of the seriousness of this safety concern and the similarities between the two types of cancer for which this drug is approved and the type of cancer that was studied in the clinical trial, we are alerting patients and health care professionals that we are reevaluating this risk against the benefits of Ukoniq [umbralisib] for its approved uses,” the FDA safety communication states.

The FDA said it performed an initial review of data from the phase 3, randomized controlled UNITY trial, which is evaluating the efficacy of umbralisib plus a monoclonal antibody in patients with chronic lymphocytic leukemia.

“The results showed a possible increased risk of death in patients receiving the combination of Ukoniq [umbralisib] and the monoclonal antibody compared to the control arm,” according to the FDA. “Those receiving the combination of Ukoniq [umbralisib] and the monoclonal antibody also experienced more serious adverse events than those in the control arm.”

Although the drug has not been approved for patients with chronic lymphocytic leukemia, the FDA believes the findings could “have implications for its approved uses” in marginal zone lymphoma and follicular lymphoma.

However, the phase 2 trial that led to February 2021 approvals found the drug’s safety profile to be “manageable,” with serious adverse reactions reported in 18% of patients receiving the dual oral inhibitor of phosphoinositide 3 kinase delta and casein kinase 1 epsilon. These adverse reactions included diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%); however, no elevated risk of death was indicated in that analysis.

The FDA noted it will continue to evaluate the results from the phase 3 UNITY trial in chronic lymphocytic leukemia and has suspended enrollment of new patients in other ongoing clinical trials of the drug.

The FDA stated that it would communicate its “final conclusions and recommendations when we have completed our review.” In the meantime, the agency asks health care professionals to review how patients receiving umbralisib are faring and discuss “the risks and benefits of continuing” versus switching to other treatments.

The FDA also asks clinicians and patients to report side effects involving the drug to the FDA MedWatch program.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration announced on Feb. 3 its investigation into “a possible increased risk of death” associated with the lymphoma drug umbralisib (Ukoniq).

The FDA granted accelerated approval to umbralisib in February 2021 for patients with two types of lymphoma: Adults with relapsed or refractory marginal zone lymphoma who received at least one prior therapy, and those with relapsed or refractory follicular lymphoma who received at least three prior therapies.

According to the FDA, the possible increased risk of death arose from early findings in a phase 3 trial evaluating the drug in a related type of cancer: chronic lymphocytic leukemia.

“Because of the seriousness of this safety concern and the similarities between the two types of cancer for which this drug is approved and the type of cancer that was studied in the clinical trial, we are alerting patients and health care professionals that we are reevaluating this risk against the benefits of Ukoniq [umbralisib] for its approved uses,” the FDA safety communication states.

The FDA said it performed an initial review of data from the phase 3, randomized controlled UNITY trial, which is evaluating the efficacy of umbralisib plus a monoclonal antibody in patients with chronic lymphocytic leukemia.

“The results showed a possible increased risk of death in patients receiving the combination of Ukoniq [umbralisib] and the monoclonal antibody compared to the control arm,” according to the FDA. “Those receiving the combination of Ukoniq [umbralisib] and the monoclonal antibody also experienced more serious adverse events than those in the control arm.”

Although the drug has not been approved for patients with chronic lymphocytic leukemia, the FDA believes the findings could “have implications for its approved uses” in marginal zone lymphoma and follicular lymphoma.

However, the phase 2 trial that led to February 2021 approvals found the drug’s safety profile to be “manageable,” with serious adverse reactions reported in 18% of patients receiving the dual oral inhibitor of phosphoinositide 3 kinase delta and casein kinase 1 epsilon. These adverse reactions included diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%); however, no elevated risk of death was indicated in that analysis.

The FDA noted it will continue to evaluate the results from the phase 3 UNITY trial in chronic lymphocytic leukemia and has suspended enrollment of new patients in other ongoing clinical trials of the drug.

The FDA stated that it would communicate its “final conclusions and recommendations when we have completed our review.” In the meantime, the agency asks health care professionals to review how patients receiving umbralisib are faring and discuss “the risks and benefits of continuing” versus switching to other treatments.

The FDA also asks clinicians and patients to report side effects involving the drug to the FDA MedWatch program.

A version of this article first appeared on Medscape.com.

Not all federal practitioners know about the National Practitioner Data Bank (NPDB), a federal web-based repository of reports containing information on medical malpractice payments and certain adverse actions related to health care practitioners, providers, and suppliers. This article explains how NPDB statutes and regulations specifically affect federal health care practitioners, which may differ from how the rules affect practitioners in the private sector.¹

National Practitioner Data Bank

Established by Congress in 1986, the NPDB contains information health care organizations need to make informed decisions about the health care practitionerss they license, credential, and hire. Federal regulations authorize eligible entities, including government agencies, to report to and query the NPDB. Individuals and organizations that are subjects of these reports have access to their own information. The reports are confidential and not available to the public. The NPDB currently contains > 1.6 million reports.²

Federal Agencies Queries

A query is a search for information in the NPDB regarding a health care practitioners or organization. Some federal agencies are permitted to query the NPDB, and all hospitals, including federal hospitals, are required to query. Agencies administering government health care programs (including private entities administering such programs under contract), federal law enforcement officials and agencies, and federal agencies responsible for the licensing or certification of health care practitioners, health care providers, or health care suppliers may query NPDB. Information received in response to queries includes, among other actions, licensure and certification actions taken by states, medical malpractice payment information, federal licensing and certification actions, and adverse privileging actions.³

Federal Reporting Requirements

Federal government agencies must report exclusions (described below), adjudicated actions, civil judgments, and criminal convictions concerning health care practitioners, providers, or suppliers. The following provides detailed information about the actions federal government agencies are required to report.

Adjudicated Actions or Decisions

Adjudicated actions or decisions are formal or official final actions.³ They include, but are not limited to, personnel-related actions such as suspensions without pay, reductions in pay, reductions in grade for cause, terminations, or other comparable actions. To be reportable, adjudicated actions or decisions must include due process mechanisms. Whether the subject of a report elects not to use the due process mechanism is immaterial as long as such a process is available to the subject before the adjudicated action or decision is made final. In general, if an adjudicated action or decision follows an agency’s established administrative procedures and those procedures ensure that due process is available to the subject, the due process requirement is satisfied. This definition specifically excludes clinical privileging actions taken by federal government agencies, which are described in appropriate memorandums of understanding.

Exclusions

An exclusion is a temporary or permanent debarment of an individual or organization from participation in a federal health-related program, such that items or services furnished by the individual or organization will not be reimbursed under the federal program.³

Civil Judgments and Criminal Convictions

Health care–related civil judgments and settlements must be reported.However, settlements in which no findings of liability have been made are not reportable.³ Health care–related criminal convictions prosecuted by federal government agencies in federal court must be reported to the NPDB. Pleas of guilt and nolo contendere, or no contest, by individuals or organizations also are reportable.³

In addition, final adverse licensure and certification actions are those taken against health care practitioners, providers, or suppliers, regardless of whether the final adverse action is the subject of a pending appeal.³ These must be reported.

Additional Reporting Requirements

Federal hospitals or federal government agencies administering health care services may have additional reporting requirements besides reporting adjudicated actions, exclusions, civil judgments, and criminal convictions. They may include submitting reports under a memorandum of understanding on clinical privileges actions and medical malpractice payments.³ The US Department of Health and Human Services (HHS) has entered into memorandums of understanding with the US Department of Defense and the US Department of Veteran Affairs to ensure their participation in the NPDB system. Federal hospitals should refer to applicable memorandums of understanding and agency-specific policies for guidance on carrying out their reporting responsibilities.⁴

Responding to a Report

The NPDB sends a letter to health care practitioners when an organization submits a report about the practitioner. The letter has the report number and a password is required to view the report.² Health care practitioners also can order a self-query online to view any reports on them in the NPDB.

The subject of the report can also add a statement and dispute the report. The statement is an opportunity to provide additional information the subject would like to have included in the report. If the subject disagrees with the accuracy of a report or believes it does not meet NPDB reporting requirements, it can be disputed. The dispute will become part of the report. When the subject adds a statement or dispute, the NPDB notifies the reporting organization and all organizations that received the report within the previous 3 years of the report activity.

Health care practitioners must contact the reporting organization to try to resolve their dispute. If the subject of the report has contacted or tried to contact the reporting organization and could not resolve the dispute after 60 days, or if, within the 60-day period, the organization informs the subject that it will not modify the report, that individual may request dispute resolution.Requesting dispute resolution does not remove the report from the NPDB.

Dispute Resolution

Dispute resolution is a request for the HHS secretary to review the report. The secretary authorizes the Division of Practitioner Data Bank (DPDB) to conduct this review. The DPDB is responsible for oversight of the NPDB. The subject of the report will need to submit relevant supporting documentation to request dispute resolution. This documentation should show that the information in the report is not accurate or that the action is not reportable. Also, proof should be included that the subject contacted or attempted to contact the reporting organization. Submitting large volumes or extraneous documentation can delay the review process.

A dispute resolution manager will review the case and send the reporting organization a request for information if needed. The DPDB will send the subject of the report a courtesy copy of all correspondence. The dispute resolution timeline varies, as the DPDB reviews disputes in the order they are received. It completes a fair and thorough review based on the unique circumstances of each case and will review the case as soon as possible. Once the DPDB receives documentation from the subject and the reporting organization, it reviews the documentation to determine whether the report accurately reflects the record.

The DPDB decides to either maintain the report as is, correct it, or remove it from the NPDB. Once the process is complete, the dispute resolution manager sends a decision letter to the subject of the report and the reporting organization. The dispute resolution decision will appear in the report.

Not all federal practitioners know about the National Practitioner Data Bank (NPDB), a federal web-based repository of reports containing information on medical malpractice payments and certain adverse actions related to health care practitioners, providers, and suppliers. This article explains how NPDB statutes and regulations specifically affect federal health care practitioners, which may differ from how the rules affect practitioners in the private sector.¹

National Practitioner Data Bank

Established by Congress in 1986, the NPDB contains information health care organizations need to make informed decisions about the health care practitionerss they license, credential, and hire. Federal regulations authorize eligible entities, including government agencies, to report to and query the NPDB. Individuals and organizations that are subjects of these reports have access to their own information. The reports are confidential and not available to the public. The NPDB currently contains > 1.6 million reports.²

Federal Agencies Queries

A query is a search for information in the NPDB regarding a health care practitioners or organization. Some federal agencies are permitted to query the NPDB, and all hospitals, including federal hospitals, are required to query. Agencies administering government health care programs (including private entities administering such programs under contract), federal law enforcement officials and agencies, and federal agencies responsible for the licensing or certification of health care practitioners, health care providers, or health care suppliers may query NPDB. Information received in response to queries includes, among other actions, licensure and certification actions taken by states, medical malpractice payment information, federal licensing and certification actions, and adverse privileging actions.³

Federal Reporting Requirements

Federal government agencies must report exclusions (described below), adjudicated actions, civil judgments, and criminal convictions concerning health care practitioners, providers, or suppliers. The following provides detailed information about the actions federal government agencies are required to report.

Adjudicated Actions or Decisions

Adjudicated actions or decisions are formal or official final actions.³ They include, but are not limited to, personnel-related actions such as suspensions without pay, reductions in pay, reductions in grade for cause, terminations, or other comparable actions. To be reportable, adjudicated actions or decisions must include due process mechanisms. Whether the subject of a report elects not to use the due process mechanism is immaterial as long as such a process is available to the subject before the adjudicated action or decision is made final. In general, if an adjudicated action or decision follows an agency’s established administrative procedures and those procedures ensure that due process is available to the subject, the due process requirement is satisfied. This definition specifically excludes clinical privileging actions taken by federal government agencies, which are described in appropriate memorandums of understanding.

Exclusions

An exclusion is a temporary or permanent debarment of an individual or organization from participation in a federal health-related program, such that items or services furnished by the individual or organization will not be reimbursed under the federal program.³

Civil Judgments and Criminal Convictions

Health care–related civil judgments and settlements must be reported.However, settlements in which no findings of liability have been made are not reportable.³ Health care–related criminal convictions prosecuted by federal government agencies in federal court must be reported to the NPDB. Pleas of guilt and nolo contendere, or no contest, by individuals or organizations also are reportable.³

In addition, final adverse licensure and certification actions are those taken against health care practitioners, providers, or suppliers, regardless of whether the final adverse action is the subject of a pending appeal.³ These must be reported.

Additional Reporting Requirements

Federal hospitals or federal government agencies administering health care services may have additional reporting requirements besides reporting adjudicated actions, exclusions, civil judgments, and criminal convictions. They may include submitting reports under a memorandum of understanding on clinical privileges actions and medical malpractice payments.³ The US Department of Health and Human Services (HHS) has entered into memorandums of understanding with the US Department of Defense and the US Department of Veteran Affairs to ensure their participation in the NPDB system. Federal hospitals should refer to applicable memorandums of understanding and agency-specific policies for guidance on carrying out their reporting responsibilities.⁴

Responding to a Report

The NPDB sends a letter to health care practitioners when an organization submits a report about the practitioner. The letter has the report number and a password is required to view the report.² Health care practitioners also can order a self-query online to view any reports on them in the NPDB.

The subject of the report can also add a statement and dispute the report. The statement is an opportunity to provide additional information the subject would like to have included in the report. If the subject disagrees with the accuracy of a report or believes it does not meet NPDB reporting requirements, it can be disputed. The dispute will become part of the report. When the subject adds a statement or dispute, the NPDB notifies the reporting organization and all organizations that received the report within the previous 3 years of the report activity.

Health care practitioners must contact the reporting organization to try to resolve their dispute. If the subject of the report has contacted or tried to contact the reporting organization and could not resolve the dispute after 60 days, or if, within the 60-day period, the organization informs the subject that it will not modify the report, that individual may request dispute resolution.Requesting dispute resolution does not remove the report from the NPDB.

Dispute Resolution

Dispute resolution is a request for the HHS secretary to review the report. The secretary authorizes the Division of Practitioner Data Bank (DPDB) to conduct this review. The DPDB is responsible for oversight of the NPDB. The subject of the report will need to submit relevant supporting documentation to request dispute resolution. This documentation should show that the information in the report is not accurate or that the action is not reportable. Also, proof should be included that the subject contacted or attempted to contact the reporting organization. Submitting large volumes or extraneous documentation can delay the review process.

A dispute resolution manager will review the case and send the reporting organization a request for information if needed. The DPDB will send the subject of the report a courtesy copy of all correspondence. The dispute resolution timeline varies, as the DPDB reviews disputes in the order they are received. It completes a fair and thorough review based on the unique circumstances of each case and will review the case as soon as possible. Once the DPDB receives documentation from the subject and the reporting organization, it reviews the documentation to determine whether the report accurately reflects the record.

The DPDB decides to either maintain the report as is, correct it, or remove it from the NPDB. Once the process is complete, the dispute resolution manager sends a decision letter to the subject of the report and the reporting organization. The dispute resolution decision will appear in the report.

Not all federal practitioners know about the National Practitioner Data Bank (NPDB), a federal web-based repository of reports containing information on medical malpractice payments and certain adverse actions related to health care practitioners, providers, and suppliers. This article explains how NPDB statutes and regulations specifically affect federal health care practitioners, which may differ from how the rules affect practitioners in the private sector.¹

National Practitioner Data Bank

Established by Congress in 1986, the NPDB contains information health care organizations need to make informed decisions about the health care practitionerss they license, credential, and hire. Federal regulations authorize eligible entities, including government agencies, to report to and query the NPDB. Individuals and organizations that are subjects of these reports have access to their own information. The reports are confidential and not available to the public. The NPDB currently contains > 1.6 million reports.²

Federal Agencies Queries

A query is a search for information in the NPDB regarding a health care practitioners or organization. Some federal agencies are permitted to query the NPDB, and all hospitals, including federal hospitals, are required to query. Agencies administering government health care programs (including private entities administering such programs under contract), federal law enforcement officials and agencies, and federal agencies responsible for the licensing or certification of health care practitioners, health care providers, or health care suppliers may query NPDB. Information received in response to queries includes, among other actions, licensure and certification actions taken by states, medical malpractice payment information, federal licensing and certification actions, and adverse privileging actions.³

Federal Reporting Requirements

Federal government agencies must report exclusions (described below), adjudicated actions, civil judgments, and criminal convictions concerning health care practitioners, providers, or suppliers. The following provides detailed information about the actions federal government agencies are required to report.

Adjudicated Actions or Decisions

Adjudicated actions or decisions are formal or official final actions.³ They include, but are not limited to, personnel-related actions such as suspensions without pay, reductions in pay, reductions in grade for cause, terminations, or other comparable actions. To be reportable, adjudicated actions or decisions must include due process mechanisms. Whether the subject of a report elects not to use the due process mechanism is immaterial as long as such a process is available to the subject before the adjudicated action or decision is made final. In general, if an adjudicated action or decision follows an agency’s established administrative procedures and those procedures ensure that due process is available to the subject, the due process requirement is satisfied. This definition specifically excludes clinical privileging actions taken by federal government agencies, which are described in appropriate memorandums of understanding.

Exclusions

An exclusion is a temporary or permanent debarment of an individual or organization from participation in a federal health-related program, such that items or services furnished by the individual or organization will not be reimbursed under the federal program.³

Civil Judgments and Criminal Convictions

Health care–related civil judgments and settlements must be reported.However, settlements in which no findings of liability have been made are not reportable.³ Health care–related criminal convictions prosecuted by federal government agencies in federal court must be reported to the NPDB. Pleas of guilt and nolo contendere, or no contest, by individuals or organizations also are reportable.³

In addition, final adverse licensure and certification actions are those taken against health care practitioners, providers, or suppliers, regardless of whether the final adverse action is the subject of a pending appeal.³ These must be reported.

Additional Reporting Requirements

Federal hospitals or federal government agencies administering health care services may have additional reporting requirements besides reporting adjudicated actions, exclusions, civil judgments, and criminal convictions. They may include submitting reports under a memorandum of understanding on clinical privileges actions and medical malpractice payments.³ The US Department of Health and Human Services (HHS) has entered into memorandums of understanding with the US Department of Defense and the US Department of Veteran Affairs to ensure their participation in the NPDB system. Federal hospitals should refer to applicable memorandums of understanding and agency-specific policies for guidance on carrying out their reporting responsibilities.⁴

Responding to a Report

The NPDB sends a letter to health care practitioners when an organization submits a report about the practitioner. The letter has the report number and a password is required to view the report.² Health care practitioners also can order a self-query online to view any reports on them in the NPDB.

The subject of the report can also add a statement and dispute the report. The statement is an opportunity to provide additional information the subject would like to have included in the report. If the subject disagrees with the accuracy of a report or believes it does not meet NPDB reporting requirements, it can be disputed. The dispute will become part of the report. When the subject adds a statement or dispute, the NPDB notifies the reporting organization and all organizations that received the report within the previous 3 years of the report activity.

Health care practitioners must contact the reporting organization to try to resolve their dispute. If the subject of the report has contacted or tried to contact the reporting organization and could not resolve the dispute after 60 days, or if, within the 60-day period, the organization informs the subject that it will not modify the report, that individual may request dispute resolution.Requesting dispute resolution does not remove the report from the NPDB.

Dispute Resolution

Dispute resolution is a request for the HHS secretary to review the report. The secretary authorizes the Division of Practitioner Data Bank (DPDB) to conduct this review. The DPDB is responsible for oversight of the NPDB. The subject of the report will need to submit relevant supporting documentation to request dispute resolution. This documentation should show that the information in the report is not accurate or that the action is not reportable. Also, proof should be included that the subject contacted or attempted to contact the reporting organization. Submitting large volumes or extraneous documentation can delay the review process.

A dispute resolution manager will review the case and send the reporting organization a request for information if needed. The DPDB will send the subject of the report a courtesy copy of all correspondence. The dispute resolution timeline varies, as the DPDB reviews disputes in the order they are received. It completes a fair and thorough review based on the unique circumstances of each case and will review the case as soon as possible. Once the DPDB receives documentation from the subject and the reporting organization, it reviews the documentation to determine whether the report accurately reflects the record.

The DPDB decides to either maintain the report as is, correct it, or remove it from the NPDB. Once the process is complete, the dispute resolution manager sends a decision letter to the subject of the report and the reporting organization. The dispute resolution decision will appear in the report.

Opioid overdose is a major public health challenge, with recent reports estimating 41 deaths per day in the United States from prescription opioid overdose.^1,2 Prescribing naloxone has increasingly been advocated to reduce the risk of opioid overdose for patients identified as high risk. Naloxone distribution has been shown to decrease the incidence of opioid overdoses in the general population.^3,4 The Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain recommends considering naloxone prescription for patients with a history of overdose or substance use disorder, opioid dosages ≥ 50 morphine equivalent daily dose (MEDD), and concurrent use of benzodiazepines.⁵

Although the CDC guidelines are intended for primary care clinicians in outpatient settings, naloxone prescribing is also relevant in the postsurgical setting.⁵ Many surgical patients are at risk for opioid overdose and data from the Veterans Health Administration (VHA) has shown that risk of opioid overdose is 11-fold higher in the 30 days following discharge from a surgical admission, when compared with the subsequent calendar year.^6,7 This likely occurs due to new prescriptions or escalated doses of opioids following surgery. Overdose risk may be particularly relevant to orthopedic surgery as postoperative opioids are commonly prescribed.⁸ Patients undergoing total knee arthroplasty (TKA) may represent a vulnerable population to overdose as it is one of the most commonly performed surgeries for the treatment of chronic pain, and is frequently performed in older adults with medical comorbidities.^9,10

Identifying patients at high risk for opioid overdose is important for targeted naloxone dispensing.⁵ A risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) tool has been developed and validated in veteran and other populations to identify such patients.¹¹ The RIOSORD tool classifies patients by risk level (1-10) and predicts probability of overdose or serious opioid-induced respiratory depression (OSORD). A patient’s level of risk is based on a weighted combination of the 15 independent risk factors most highly associated with OSORD, including comorbid conditions, prescription drug use, and health care utilization.¹² Using the RIOSORD tool, the VHA Opioid Education and Naloxone Distribution (OEND) program is a risk mitigation initiative that aims to decrease opioid-related overdose morbidity and mortality. This is achieved via opioid overdose education for prevention, recognition, and response and includes outpatient naloxone prescription.^13,14

Despite the comprehensive OEND program, there exists very little data to guide postsurgical naloxone prescribing. The prevalence of known risk factors for overdose in surgical patients remains unknown, as does the prevalence of perioperative naloxone distribution. Understanding overdose risk factors and naloxone prescribing patterns in surgical patients may identify potential targets for OEND efforts. This study retrospectively estimated RIOSORD scores for TKA patients between 2013 to 2016 and described naloxone distribution based on RIOSORD scores and risk factors.

Methods

We identified patients who had undergone primary TKA at VHA hospitals using Current Procedural Terminology (CPT), International Classification of Diseases, Ninth Revision (ICD-9) procedure codes, and data extracted from the VHA Corporate Data Warehouse (CDW) of electronic health records (EHRs). Our study was granted approval with exemption from informed consent by the Durham Veteran Affairs Healthcare System Institutional Review Board.

This retrospective cohort study included all veterans who underwent elective primary TKA from January 1, 2013 through December 31, 2016. We excluded patients who died before discharge.

Outcomes

Our primary outcome was being dispensed an outpatient naloxone prescription following TKA. Naloxone dispensing was identified by examining CDW outpatient pharmacy records with a final dispense date from 1 year before surgery through 7 days after discharge following TKA. To exclude naloxone administration that may have been given in a clinic, prescription data included only records with an outpatient prescription copay. Naloxone dispensing in the year before surgery was chosen to estimate likely preoperative possession of naloxone which could be available in the postoperative period. Naloxone dispensing until 7 days after discharge was chosen to identify any new dispensing that would be available in the postoperative period. These outcomes were examined over the study time frame on an annual basis.

Patient Factors

Demographic variables included age, sex, and race/ethnicity. Independent risk factors for overdose from RIOSORD were identified for each patient.¹⁵ These risk factors included comorbidities (opioid use disorder, schizophrenia, bipolar disorder, liver disease, chronic kidney disease, sleep apnea, or lung disease) and prescription drug use (use of opioids, benzodiazepines, long-acting opioids, ≥ 50 MEDD or ≥ 100 MEDD). ICD-9 and ICD-10 diagnosis codes were used to identify comorbidities. Risk classes on day of surgery were identified using a RIOSORD algorithm code. Consistent with the display of RIOSORD risk classes on the VHA Academic Detailing Service OEND risk report, patients were grouped into 3 groups based on their RIOSORD score: classes 1 to 4 (low risk), 5 to 7 (moderate risk), and 8 to 10 (high risk).

Descriptive statistics were used to summarize data on patient demographics, RIOSORD risk factors, overdose events, and naloxone dispensing over time.

Results

The study cohort included 38,011 veterans who underwent primary TKA in the VHA between January 1, 2013 and December 30, 2016. In this cohort, the mean age was 65 years, 93% were male, and 77% were White patients (Table 1). The most common comorbidities were lung disease in 9170 (24.1%) patients, sleep apnea in 6630 (17.4%) patients, chronic kidney disease in 4036 (10.6%) patients, liver disease in 2822 (7.4%) patients, and bipolar disorder in 1748 (4.6%) patients.

In 2013, 63.1% of patients presenting for surgery were actively prescribed opioids. By 2016, this decreased to 50.5%. Benzodiazepine use decreased from 13.2 to 8.8% and long-acting opioid use decreased from 8.5 to 5.8% over the same period. Patients taking ≥ 50 MEDD decreased from 8.0 to 5.3% and patients taking ≥ 100 MEDD decreased from 3.3 to 2.2%. The prevalence of moderate-risk patients decreased from 2.5 to 1.6% and high-risk patients decreased from 0.8 to 0.6% (Figure 1). Cumulatively, the prevalence of presenting with either moderate or high risk of overdose decreased from 3.3 to 2.2% between 2013 to 2016.

Naloxone Dispensing

In 2013, naloxone was not dispensed to any patients at moderate or high risk for overdose between 365 days prior to surgery until 7 days after discharge (Table 2 and Figure 2). Low-risk group naloxone dispensing increased to 2 (0.0%) in 2014, to 13 (0.1%), in 2015, and to 86 (0.9%) in 2016. Moderate-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 8 (3.5%) in 2015, and to 18 (10.9%) in 2016. High-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 5 (5.8%) in 2015, and to 8 (12.7%) in 2016 (Figure 3).

Discussion

Our data demonstrate that patients presenting for TKA between 2013 and 2016 routinely had individual risk factors for overdose related to either prescription drug use or comorbidities. We also show that, although the number of patients at moderate and high risk for opioid overdose is decreasing, 2.2% of TKA patients remain at moderate or high risk for opioid overdose based on a weighted combination of these individual risk factors using RIOSORD. As demand for primary TKA is projected to grow to 3.5 million procedures by 2030, using prevalence from 2016, we estimate that 76,560 patients may present for TKA across the US with moderate or high risk for opioid overdose.⁹ Following discharge, this risk may be even higher as this estimate does not yet account for postoperative opioid use. We demonstrate that through a VHA OEND initiative, naloxone distribution increased and appeared to be targeted to those most at risk using a simple validated tool like RIOSORD.

Presence of an individual risk factor for overdose was present in as many as 63.1% of patients presenting for TKA, as was seen in 2013 with preoperative opioid use. The 3 highest scoring prescription use–related risk factors in RIOSORD are use of opioids ≥ 100 MEDD (16 points), ≥ 50 MEDD (9 points), and long-acting formulations (9 points). All 3 decreased in prevalence over the study period but by 2016 were still seen in 2.2% for ≥ 100 MEDD, 5.3% for ≥ 50 MEDD, and 5.8% for long-acting opioids. This decrease was not surprising given implementation of a VHA-wide opioid safety initiative and the OEND program, but this could also be related to changes in patient selection for surgery in the context of increased awareness of the opioid epidemic. Despite the trend toward safer opioid prescribing, by 2016 over half of patients (50.5%) who presented for TKA were already taking opioids, with 10.6% (543 of 5127) on doses ≥ 50 MEDD.

We observed a decrease in RIOSORD risk each year, consistent with decreasing prescription-related risk factors over time. This was most obvious in the moderate-risk group. It is unclear why a similar decrease was not as obvious in the high-risk group, but this in part may be due to the already low numbers of patients in the high-risk group. This may also represent the high-risk group being somewhat resistant to the initiatives that shifted moderate-risk patients to the low-risk group. There were proportionately more patients in the moderate- and high-risk groups in the original RIOSORD population than in our surgical population, which may be attributed to the fewer comorbidities seen in our surgical population, as well as the higher opioid-prescribing patterns seen prior to the VA OEND initiative.¹²

Naloxone prescribing was rare prior to the OEND initiative and increased from 2013 to 2016. Increases were most marked in those in moderate- and high-risk groups, although naloxone prescribing also increased among the low-risk group. Integration of RIOSORD stratification into the OEND initiative likely played a role in targeting increased access to naloxone among those at highest risk of overdose. Naloxone dispensing increased for every group, although a significant proportion of moderate- and high-risk patients, 89.1% and 87.3%, respectively, were still not dispensed naloxone by 2016. Moreover, our estimates of perioperative naloxone access were likely an overestimate by including patients dispensed naloxone up to 1 year before surgery until 7 days after surgery. The aim was to include patients who may not have been prescribed naloxone postoperatively because of an existing naloxone prescription at home. Perioperative naloxone access estimates would have been even lower if a narrower window had been used to approximate perioperative access. This identifies an important gap between those who may benefit from naloxone dispensing and those who received naloxone. This in part may be because OEND has not been implemented as routinely in surgical settings as other settings (eg, primary care). OEND efforts may more effectively increase naloxone prescribing among surgical patients if these efforts were targeted at surgical and anesthesia departments. Given that the Comprehensive Addiction and Recovery Act of 2016 requires an assessment of patient risk prior to opioid prescribing and VHA efforts to increase utilization of tools like the Stratification Tool for Opioid Risk Mitigation (STORM), which estimates patient risk when initiating an opioid prescription and includes naloxone as one of many risk mitigation strategies, we anticipate that rates of naloxone prescribing will increase over time.

Limitations

Our study captures a large number of patients across VHA hospitals of varying size nationwide, including a mix of those with and without academic medical center affiliations. This veteran population may not represent the US commercially insured population (CIP). Zedler and colleagues highlighted the differences in prevalence of individual risk factors: notably, the CIP had a substantially higher proportion of females and younger patients.¹¹ VHA had a greater prevalence of common chronic conditions associated with older age. The frequency of opioid dependence was similar among CIP and VHA. However, substance abuse and nonopioid substance dependence diagnoses were 4-fold more frequent among VHA controls as CIP controls. Prescribing of all opioids, except morphine and methadone, was substantially greater in CIP than in VHA.¹¹ Despite a difference in individual risk factors, a CIP-specific RIOSORD has been validated and can be used outside of the VHA to obviate the limitations of the VHA-specific RIOSORD.¹¹

Other limitations include our estimation of naloxone access. We do not know whether naloxone was administered or have a reliable estimate of overdose incidence in this postoperative TKA population. Also, it is important to note that RIOSORD was not developed for surgical patients. The use of RIOSORD in a postoperative population likely underestimates risk of opioid overdose due to the frequent prescriptions of new opioids or escalation of existing MEDD to the postoperative patient. Our study was also retrospective in nature and reliant on accurate coding of patient risk factors. It is possible that comorbidities were not accurately identified by EHR and therefore subject to inconsistency.

Conclusions

Veterans presenting for TKA routinely have risk factors for opioid overdose. We observed a trend toward decreasing overdose risk which coincided with the Opioid Safety and OEND initiatives within the VHA. We also observed an increase in naloxone prescription for moderate- and high-risk patients undergoing TKA, although most of these patients still did not receive naloxone as of 2016. More research is needed to refine and validate the RIOSORD score for surgical populations. Expanding initiatives such as OEND to include surgical patients presents an opportunity to improve access to naloxone for postoperative patients that may help reduce opioid overdose in this population.

Opioid overdose is a major public health challenge, with recent reports estimating 41 deaths per day in the United States from prescription opioid overdose.^1,2 Prescribing naloxone has increasingly been advocated to reduce the risk of opioid overdose for patients identified as high risk. Naloxone distribution has been shown to decrease the incidence of opioid overdoses in the general population.^3,4 The Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain recommends considering naloxone prescription for patients with a history of overdose or substance use disorder, opioid dosages ≥ 50 morphine equivalent daily dose (MEDD), and concurrent use of benzodiazepines.⁵

Although the CDC guidelines are intended for primary care clinicians in outpatient settings, naloxone prescribing is also relevant in the postsurgical setting.⁵ Many surgical patients are at risk for opioid overdose and data from the Veterans Health Administration (VHA) has shown that risk of opioid overdose is 11-fold higher in the 30 days following discharge from a surgical admission, when compared with the subsequent calendar year.^6,7 This likely occurs due to new prescriptions or escalated doses of opioids following surgery. Overdose risk may be particularly relevant to orthopedic surgery as postoperative opioids are commonly prescribed.⁸ Patients undergoing total knee arthroplasty (TKA) may represent a vulnerable population to overdose as it is one of the most commonly performed surgeries for the treatment of chronic pain, and is frequently performed in older adults with medical comorbidities.^9,10

Identifying patients at high risk for opioid overdose is important for targeted naloxone dispensing.⁵ A risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) tool has been developed and validated in veteran and other populations to identify such patients.¹¹ The RIOSORD tool classifies patients by risk level (1-10) and predicts probability of overdose or serious opioid-induced respiratory depression (OSORD). A patient’s level of risk is based on a weighted combination of the 15 independent risk factors most highly associated with OSORD, including comorbid conditions, prescription drug use, and health care utilization.¹² Using the RIOSORD tool, the VHA Opioid Education and Naloxone Distribution (OEND) program is a risk mitigation initiative that aims to decrease opioid-related overdose morbidity and mortality. This is achieved via opioid overdose education for prevention, recognition, and response and includes outpatient naloxone prescription.^13,14

Despite the comprehensive OEND program, there exists very little data to guide postsurgical naloxone prescribing. The prevalence of known risk factors for overdose in surgical patients remains unknown, as does the prevalence of perioperative naloxone distribution. Understanding overdose risk factors and naloxone prescribing patterns in surgical patients may identify potential targets for OEND efforts. This study retrospectively estimated RIOSORD scores for TKA patients between 2013 to 2016 and described naloxone distribution based on RIOSORD scores and risk factors.

Methods

We identified patients who had undergone primary TKA at VHA hospitals using Current Procedural Terminology (CPT), International Classification of Diseases, Ninth Revision (ICD-9) procedure codes, and data extracted from the VHA Corporate Data Warehouse (CDW) of electronic health records (EHRs). Our study was granted approval with exemption from informed consent by the Durham Veteran Affairs Healthcare System Institutional Review Board.

This retrospective cohort study included all veterans who underwent elective primary TKA from January 1, 2013 through December 31, 2016. We excluded patients who died before discharge.

Outcomes

Our primary outcome was being dispensed an outpatient naloxone prescription following TKA. Naloxone dispensing was identified by examining CDW outpatient pharmacy records with a final dispense date from 1 year before surgery through 7 days after discharge following TKA. To exclude naloxone administration that may have been given in a clinic, prescription data included only records with an outpatient prescription copay. Naloxone dispensing in the year before surgery was chosen to estimate likely preoperative possession of naloxone which could be available in the postoperative period. Naloxone dispensing until 7 days after discharge was chosen to identify any new dispensing that would be available in the postoperative period. These outcomes were examined over the study time frame on an annual basis.

Patient Factors

Demographic variables included age, sex, and race/ethnicity. Independent risk factors for overdose from RIOSORD were identified for each patient.¹⁵ These risk factors included comorbidities (opioid use disorder, schizophrenia, bipolar disorder, liver disease, chronic kidney disease, sleep apnea, or lung disease) and prescription drug use (use of opioids, benzodiazepines, long-acting opioids, ≥ 50 MEDD or ≥ 100 MEDD). ICD-9 and ICD-10 diagnosis codes were used to identify comorbidities. Risk classes on day of surgery were identified using a RIOSORD algorithm code. Consistent with the display of RIOSORD risk classes on the VHA Academic Detailing Service OEND risk report, patients were grouped into 3 groups based on their RIOSORD score: classes 1 to 4 (low risk), 5 to 7 (moderate risk), and 8 to 10 (high risk).

Descriptive statistics were used to summarize data on patient demographics, RIOSORD risk factors, overdose events, and naloxone dispensing over time.

Results

The study cohort included 38,011 veterans who underwent primary TKA in the VHA between January 1, 2013 and December 30, 2016. In this cohort, the mean age was 65 years, 93% were male, and 77% were White patients (Table 1). The most common comorbidities were lung disease in 9170 (24.1%) patients, sleep apnea in 6630 (17.4%) patients, chronic kidney disease in 4036 (10.6%) patients, liver disease in 2822 (7.4%) patients, and bipolar disorder in 1748 (4.6%) patients.

In 2013, 63.1% of patients presenting for surgery were actively prescribed opioids. By 2016, this decreased to 50.5%. Benzodiazepine use decreased from 13.2 to 8.8% and long-acting opioid use decreased from 8.5 to 5.8% over the same period. Patients taking ≥ 50 MEDD decreased from 8.0 to 5.3% and patients taking ≥ 100 MEDD decreased from 3.3 to 2.2%. The prevalence of moderate-risk patients decreased from 2.5 to 1.6% and high-risk patients decreased from 0.8 to 0.6% (Figure 1). Cumulatively, the prevalence of presenting with either moderate or high risk of overdose decreased from 3.3 to 2.2% between 2013 to 2016.

Naloxone Dispensing

In 2013, naloxone was not dispensed to any patients at moderate or high risk for overdose between 365 days prior to surgery until 7 days after discharge (Table 2 and Figure 2). Low-risk group naloxone dispensing increased to 2 (0.0%) in 2014, to 13 (0.1%), in 2015, and to 86 (0.9%) in 2016. Moderate-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 8 (3.5%) in 2015, and to 18 (10.9%) in 2016. High-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 5 (5.8%) in 2015, and to 8 (12.7%) in 2016 (Figure 3).

Discussion

Our data demonstrate that patients presenting for TKA between 2013 and 2016 routinely had individual risk factors for overdose related to either prescription drug use or comorbidities. We also show that, although the number of patients at moderate and high risk for opioid overdose is decreasing, 2.2% of TKA patients remain at moderate or high risk for opioid overdose based on a weighted combination of these individual risk factors using RIOSORD. As demand for primary TKA is projected to grow to 3.5 million procedures by 2030, using prevalence from 2016, we estimate that 76,560 patients may present for TKA across the US with moderate or high risk for opioid overdose.⁹ Following discharge, this risk may be even higher as this estimate does not yet account for postoperative opioid use. We demonstrate that through a VHA OEND initiative, naloxone distribution increased and appeared to be targeted to those most at risk using a simple validated tool like RIOSORD.

Presence of an individual risk factor for overdose was present in as many as 63.1% of patients presenting for TKA, as was seen in 2013 with preoperative opioid use. The 3 highest scoring prescription use–related risk factors in RIOSORD are use of opioids ≥ 100 MEDD (16 points), ≥ 50 MEDD (9 points), and long-acting formulations (9 points). All 3 decreased in prevalence over the study period but by 2016 were still seen in 2.2% for ≥ 100 MEDD, 5.3% for ≥ 50 MEDD, and 5.8% for long-acting opioids. This decrease was not surprising given implementation of a VHA-wide opioid safety initiative and the OEND program, but this could also be related to changes in patient selection for surgery in the context of increased awareness of the opioid epidemic. Despite the trend toward safer opioid prescribing, by 2016 over half of patients (50.5%) who presented for TKA were already taking opioids, with 10.6% (543 of 5127) on doses ≥ 50 MEDD.

We observed a decrease in RIOSORD risk each year, consistent with decreasing prescription-related risk factors over time. This was most obvious in the moderate-risk group. It is unclear why a similar decrease was not as obvious in the high-risk group, but this in part may be due to the already low numbers of patients in the high-risk group. This may also represent the high-risk group being somewhat resistant to the initiatives that shifted moderate-risk patients to the low-risk group. There were proportionately more patients in the moderate- and high-risk groups in the original RIOSORD population than in our surgical population, which may be attributed to the fewer comorbidities seen in our surgical population, as well as the higher opioid-prescribing patterns seen prior to the VA OEND initiative.¹²

Naloxone prescribing was rare prior to the OEND initiative and increased from 2013 to 2016. Increases were most marked in those in moderate- and high-risk groups, although naloxone prescribing also increased among the low-risk group. Integration of RIOSORD stratification into the OEND initiative likely played a role in targeting increased access to naloxone among those at highest risk of overdose. Naloxone dispensing increased for every group, although a significant proportion of moderate- and high-risk patients, 89.1% and 87.3%, respectively, were still not dispensed naloxone by 2016. Moreover, our estimates of perioperative naloxone access were likely an overestimate by including patients dispensed naloxone up to 1 year before surgery until 7 days after surgery. The aim was to include patients who may not have been prescribed naloxone postoperatively because of an existing naloxone prescription at home. Perioperative naloxone access estimates would have been even lower if a narrower window had been used to approximate perioperative access. This identifies an important gap between those who may benefit from naloxone dispensing and those who received naloxone. This in part may be because OEND has not been implemented as routinely in surgical settings as other settings (eg, primary care). OEND efforts may more effectively increase naloxone prescribing among surgical patients if these efforts were targeted at surgical and anesthesia departments. Given that the Comprehensive Addiction and Recovery Act of 2016 requires an assessment of patient risk prior to opioid prescribing and VHA efforts to increase utilization of tools like the Stratification Tool for Opioid Risk Mitigation (STORM), which estimates patient risk when initiating an opioid prescription and includes naloxone as one of many risk mitigation strategies, we anticipate that rates of naloxone prescribing will increase over time.

Limitations

Our study captures a large number of patients across VHA hospitals of varying size nationwide, including a mix of those with and without academic medical center affiliations. This veteran population may not represent the US commercially insured population (CIP). Zedler and colleagues highlighted the differences in prevalence of individual risk factors: notably, the CIP had a substantially higher proportion of females and younger patients.¹¹ VHA had a greater prevalence of common chronic conditions associated with older age. The frequency of opioid dependence was similar among CIP and VHA. However, substance abuse and nonopioid substance dependence diagnoses were 4-fold more frequent among VHA controls as CIP controls. Prescribing of all opioids, except morphine and methadone, was substantially greater in CIP than in VHA.¹¹ Despite a difference in individual risk factors, a CIP-specific RIOSORD has been validated and can be used outside of the VHA to obviate the limitations of the VHA-specific RIOSORD.¹¹

Other limitations include our estimation of naloxone access. We do not know whether naloxone was administered or have a reliable estimate of overdose incidence in this postoperative TKA population. Also, it is important to note that RIOSORD was not developed for surgical patients. The use of RIOSORD in a postoperative population likely underestimates risk of opioid overdose due to the frequent prescriptions of new opioids or escalation of existing MEDD to the postoperative patient. Our study was also retrospective in nature and reliant on accurate coding of patient risk factors. It is possible that comorbidities were not accurately identified by EHR and therefore subject to inconsistency.

Conclusions

Veterans presenting for TKA routinely have risk factors for opioid overdose. We observed a trend toward decreasing overdose risk which coincided with the Opioid Safety and OEND initiatives within the VHA. We also observed an increase in naloxone prescription for moderate- and high-risk patients undergoing TKA, although most of these patients still did not receive naloxone as of 2016. More research is needed to refine and validate the RIOSORD score for surgical populations. Expanding initiatives such as OEND to include surgical patients presents an opportunity to improve access to naloxone for postoperative patients that may help reduce opioid overdose in this population.

Opioid overdose is a major public health challenge, with recent reports estimating 41 deaths per day in the United States from prescription opioid overdose.^1,2 Prescribing naloxone has increasingly been advocated to reduce the risk of opioid overdose for patients identified as high risk. Naloxone distribution has been shown to decrease the incidence of opioid overdoses in the general population.^3,4 The Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain recommends considering naloxone prescription for patients with a history of overdose or substance use disorder, opioid dosages ≥ 50 morphine equivalent daily dose (MEDD), and concurrent use of benzodiazepines.⁵

Although the CDC guidelines are intended for primary care clinicians in outpatient settings, naloxone prescribing is also relevant in the postsurgical setting.⁵ Many surgical patients are at risk for opioid overdose and data from the Veterans Health Administration (VHA) has shown that risk of opioid overdose is 11-fold higher in the 30 days following discharge from a surgical admission, when compared with the subsequent calendar year.^6,7 This likely occurs due to new prescriptions or escalated doses of opioids following surgery. Overdose risk may be particularly relevant to orthopedic surgery as postoperative opioids are commonly prescribed.⁸ Patients undergoing total knee arthroplasty (TKA) may represent a vulnerable population to overdose as it is one of the most commonly performed surgeries for the treatment of chronic pain, and is frequently performed in older adults with medical comorbidities.^9,10

Identifying patients at high risk for opioid overdose is important for targeted naloxone dispensing.⁵ A risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) tool has been developed and validated in veteran and other populations to identify such patients.¹¹ The RIOSORD tool classifies patients by risk level (1-10) and predicts probability of overdose or serious opioid-induced respiratory depression (OSORD). A patient’s level of risk is based on a weighted combination of the 15 independent risk factors most highly associated with OSORD, including comorbid conditions, prescription drug use, and health care utilization.¹² Using the RIOSORD tool, the VHA Opioid Education and Naloxone Distribution (OEND) program is a risk mitigation initiative that aims to decrease opioid-related overdose morbidity and mortality. This is achieved via opioid overdose education for prevention, recognition, and response and includes outpatient naloxone prescription.^13,14

Despite the comprehensive OEND program, there exists very little data to guide postsurgical naloxone prescribing. The prevalence of known risk factors for overdose in surgical patients remains unknown, as does the prevalence of perioperative naloxone distribution. Understanding overdose risk factors and naloxone prescribing patterns in surgical patients may identify potential targets for OEND efforts. This study retrospectively estimated RIOSORD scores for TKA patients between 2013 to 2016 and described naloxone distribution based on RIOSORD scores and risk factors.

Methods

We identified patients who had undergone primary TKA at VHA hospitals using Current Procedural Terminology (CPT), International Classification of Diseases, Ninth Revision (ICD-9) procedure codes, and data extracted from the VHA Corporate Data Warehouse (CDW) of electronic health records (EHRs). Our study was granted approval with exemption from informed consent by the Durham Veteran Affairs Healthcare System Institutional Review Board.

This retrospective cohort study included all veterans who underwent elective primary TKA from January 1, 2013 through December 31, 2016. We excluded patients who died before discharge.

Outcomes

Our primary outcome was being dispensed an outpatient naloxone prescription following TKA. Naloxone dispensing was identified by examining CDW outpatient pharmacy records with a final dispense date from 1 year before surgery through 7 days after discharge following TKA. To exclude naloxone administration that may have been given in a clinic, prescription data included only records with an outpatient prescription copay. Naloxone dispensing in the year before surgery was chosen to estimate likely preoperative possession of naloxone which could be available in the postoperative period. Naloxone dispensing until 7 days after discharge was chosen to identify any new dispensing that would be available in the postoperative period. These outcomes were examined over the study time frame on an annual basis.

Patient Factors

Demographic variables included age, sex, and race/ethnicity. Independent risk factors for overdose from RIOSORD were identified for each patient.¹⁵ These risk factors included comorbidities (opioid use disorder, schizophrenia, bipolar disorder, liver disease, chronic kidney disease, sleep apnea, or lung disease) and prescription drug use (use of opioids, benzodiazepines, long-acting opioids, ≥ 50 MEDD or ≥ 100 MEDD). ICD-9 and ICD-10 diagnosis codes were used to identify comorbidities. Risk classes on day of surgery were identified using a RIOSORD algorithm code. Consistent with the display of RIOSORD risk classes on the VHA Academic Detailing Service OEND risk report, patients were grouped into 3 groups based on their RIOSORD score: classes 1 to 4 (low risk), 5 to 7 (moderate risk), and 8 to 10 (high risk).

Descriptive statistics were used to summarize data on patient demographics, RIOSORD risk factors, overdose events, and naloxone dispensing over time.

Results

The study cohort included 38,011 veterans who underwent primary TKA in the VHA between January 1, 2013 and December 30, 2016. In this cohort, the mean age was 65 years, 93% were male, and 77% were White patients (Table 1). The most common comorbidities were lung disease in 9170 (24.1%) patients, sleep apnea in 6630 (17.4%) patients, chronic kidney disease in 4036 (10.6%) patients, liver disease in 2822 (7.4%) patients, and bipolar disorder in 1748 (4.6%) patients.

In 2013, 63.1% of patients presenting for surgery were actively prescribed opioids. By 2016, this decreased to 50.5%. Benzodiazepine use decreased from 13.2 to 8.8% and long-acting opioid use decreased from 8.5 to 5.8% over the same period. Patients taking ≥ 50 MEDD decreased from 8.0 to 5.3% and patients taking ≥ 100 MEDD decreased from 3.3 to 2.2%. The prevalence of moderate-risk patients decreased from 2.5 to 1.6% and high-risk patients decreased from 0.8 to 0.6% (Figure 1). Cumulatively, the prevalence of presenting with either moderate or high risk of overdose decreased from 3.3 to 2.2% between 2013 to 2016.

Naloxone Dispensing

In 2013, naloxone was not dispensed to any patients at moderate or high risk for overdose between 365 days prior to surgery until 7 days after discharge (Table 2 and Figure 2). Low-risk group naloxone dispensing increased to 2 (0.0%) in 2014, to 13 (0.1%), in 2015, and to 86 (0.9%) in 2016. Moderate-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 8 (3.5%) in 2015, and to 18 (10.9%) in 2016. High-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 5 (5.8%) in 2015, and to 8 (12.7%) in 2016 (Figure 3).

Discussion

Our data demonstrate that patients presenting for TKA between 2013 and 2016 routinely had individual risk factors for overdose related to either prescription drug use or comorbidities. We also show that, although the number of patients at moderate and high risk for opioid overdose is decreasing, 2.2% of TKA patients remain at moderate or high risk for opioid overdose based on a weighted combination of these individual risk factors using RIOSORD. As demand for primary TKA is projected to grow to 3.5 million procedures by 2030, using prevalence from 2016, we estimate that 76,560 patients may present for TKA across the US with moderate or high risk for opioid overdose.⁹ Following discharge, this risk may be even higher as this estimate does not yet account for postoperative opioid use. We demonstrate that through a VHA OEND initiative, naloxone distribution increased and appeared to be targeted to those most at risk using a simple validated tool like RIOSORD.

Presence of an individual risk factor for overdose was present in as many as 63.1% of patients presenting for TKA, as was seen in 2013 with preoperative opioid use. The 3 highest scoring prescription use–related risk factors in RIOSORD are use of opioids ≥ 100 MEDD (16 points), ≥ 50 MEDD (9 points), and long-acting formulations (9 points). All 3 decreased in prevalence over the study period but by 2016 were still seen in 2.2% for ≥ 100 MEDD, 5.3% for ≥ 50 MEDD, and 5.8% for long-acting opioids. This decrease was not surprising given implementation of a VHA-wide opioid safety initiative and the OEND program, but this could also be related to changes in patient selection for surgery in the context of increased awareness of the opioid epidemic. Despite the trend toward safer opioid prescribing, by 2016 over half of patients (50.5%) who presented for TKA were already taking opioids, with 10.6% (543 of 5127) on doses ≥ 50 MEDD.

We observed a decrease in RIOSORD risk each year, consistent with decreasing prescription-related risk factors over time. This was most obvious in the moderate-risk group. It is unclear why a similar decrease was not as obvious in the high-risk group, but this in part may be due to the already low numbers of patients in the high-risk group. This may also represent the high-risk group being somewhat resistant to the initiatives that shifted moderate-risk patients to the low-risk group. There were proportionately more patients in the moderate- and high-risk groups in the original RIOSORD population than in our surgical population, which may be attributed to the fewer comorbidities seen in our surgical population, as well as the higher opioid-prescribing patterns seen prior to the VA OEND initiative.¹²

Naloxone prescribing was rare prior to the OEND initiative and increased from 2013 to 2016. Increases were most marked in those in moderate- and high-risk groups, although naloxone prescribing also increased among the low-risk group. Integration of RIOSORD stratification into the OEND initiative likely played a role in targeting increased access to naloxone among those at highest risk of overdose. Naloxone dispensing increased for every group, although a significant proportion of moderate- and high-risk patients, 89.1% and 87.3%, respectively, were still not dispensed naloxone by 2016. Moreover, our estimates of perioperative naloxone access were likely an overestimate by including patients dispensed naloxone up to 1 year before surgery until 7 days after surgery. The aim was to include patients who may not have been prescribed naloxone postoperatively because of an existing naloxone prescription at home. Perioperative naloxone access estimates would have been even lower if a narrower window had been used to approximate perioperative access. This identifies an important gap between those who may benefit from naloxone dispensing and those who received naloxone. This in part may be because OEND has not been implemented as routinely in surgical settings as other settings (eg, primary care). OEND efforts may more effectively increase naloxone prescribing among surgical patients if these efforts were targeted at surgical and anesthesia departments. Given that the Comprehensive Addiction and Recovery Act of 2016 requires an assessment of patient risk prior to opioid prescribing and VHA efforts to increase utilization of tools like the Stratification Tool for Opioid Risk Mitigation (STORM), which estimates patient risk when initiating an opioid prescription and includes naloxone as one of many risk mitigation strategies, we anticipate that rates of naloxone prescribing will increase over time.

Limitations

Our study captures a large number of patients across VHA hospitals of varying size nationwide, including a mix of those with and without academic medical center affiliations. This veteran population may not represent the US commercially insured population (CIP). Zedler and colleagues highlighted the differences in prevalence of individual risk factors: notably, the CIP had a substantially higher proportion of females and younger patients.¹¹ VHA had a greater prevalence of common chronic conditions associated with older age. The frequency of opioid dependence was similar among CIP and VHA. However, substance abuse and nonopioid substance dependence diagnoses were 4-fold more frequent among VHA controls as CIP controls. Prescribing of all opioids, except morphine and methadone, was substantially greater in CIP than in VHA.¹¹ Despite a difference in individual risk factors, a CIP-specific RIOSORD has been validated and can be used outside of the VHA to obviate the limitations of the VHA-specific RIOSORD.¹¹

Other limitations include our estimation of naloxone access. We do not know whether naloxone was administered or have a reliable estimate of overdose incidence in this postoperative TKA population. Also, it is important to note that RIOSORD was not developed for surgical patients. The use of RIOSORD in a postoperative population likely underestimates risk of opioid overdose due to the frequent prescriptions of new opioids or escalation of existing MEDD to the postoperative patient. Our study was also retrospective in nature and reliant on accurate coding of patient risk factors. It is possible that comorbidities were not accurately identified by EHR and therefore subject to inconsistency.

Conclusions

Veterans presenting for TKA routinely have risk factors for opioid overdose. We observed a trend toward decreasing overdose risk which coincided with the Opioid Safety and OEND initiatives within the VHA. We also observed an increase in naloxone prescription for moderate- and high-risk patients undergoing TKA, although most of these patients still did not receive naloxone as of 2016. More research is needed to refine and validate the RIOSORD score for surgical populations. Expanding initiatives such as OEND to include surgical patients presents an opportunity to improve access to naloxone for postoperative patients that may help reduce opioid overdose in this population.